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The International Journal of Molecular Sciences has published a special issue on molecular oncology, featuring nineteen articles written by leading experts in specific cancer research fields. The articles cover a wide range of topics, including cancer development, progression, and treatment options. Some of the areas explored include endoplasmic reticulum stress activation, immunotherapies, non-genetic determinants of cancer, environmental carcinogens, social stress, epigenetic reprogramming, drug resistance, microbiome modulation, tumor microenvironment, and the efficacy of ALK inhibitors. The issue also discusses the use of liposomes as a delivery strategy for chemotherapeutic drugs. The articles provide valuable insights into the global burden of cancer and offer potential avenues for further research and improved treatment options. The editorial expresses gratitude to the authors, reviewers, and editors for their contributions and hopes that the articles will promote further research in cancer treatment. [Extracted from the article]

A time-delayed virus dynamic model is proposed with general monotonic incidence, different nonlinear CTL (cytotoxic T lymphocyte) responses [CTL elimination function p y g 1 (z) and CTL stimulation function c y g 2 (z) ], and immune impairment. Indeed, the different CTL responses pose challenges in obtaining the dissipativeness of the model. By constructing appropriate Lyapunov functionals with some detailed analysis techniques, the global stability results of all equilibria of the model are obtained. By the way, we point out that the partial derivative f v (x , 0) is increasing (but not necessarily strictly) in x > 0 for the general monotonic incidence f (x , v). However, some papers defaulted that the partial derivative was strictly increasing. Our main results show that if the basic reproduction number R 0 ≤ 1 , the infection-free equilibrium E 0 is globally asymptotically stable (GAS); if CTL stimulation function c y g 2 (z) = 0 for z = 0 and the CTL threshold parameter R 1 ≤ 1 < R 0 , then the immunity-inactivated infection equilibrium E 1 is GAS; if the immunity-activated infection equilibrium E + exists, then it is GAS. Two specific examples are provided to illustrate the applicability of the main results. The main results acquired in this paper improve or extend some of the existing results. [ABSTRACT FROM AUTHOR]

As the prevalence of viral infection in body, human T‐cell leukemia virus type 1 (HTLV‐1) is receiving increasing attention. Research on the corresponding virus models is of great significance to tackle the challenges of understanding HTLV‐1 development and treatment. This paper focuses on the dynamic analysis for a stochastic model with nonlinear cytotoxic T lymphocyte (CTL) response, which is driven by Ornstein–Uhlenbeck (OU) process to model the progression of HTLV‐1 in vivo. Rich dynamic behaviors such as the extinction of infected CD4+ T cells (ITCs), stationary distribution (SD), probability density, and finite‐time stability (FTS) of the model are established to reveal the interaction of cell populations. The optimal therapeutic strategy based on the cost‐benefit viewpoint is further obtained. Finally, illustrative numerical simulations are represented to corroborate the effectiveness of treatment and the ambient perturbation's impact that strengthening the noise strength can lead to rapid virus clearance. [ABSTRACT FROM AUTHOR]

This paper explores the dynamics analysis of a human immunodeficiency virus (HIV) model with saturated cytotoxic T lymphocyte (CTL) immune response and Beddington–DeAngelis infection rate. There are two time delays in the model to describe the time needed for infection of cell and CTL immune response generation, respectively. We obtain two thresholds and three possible equilibria from the model. By analyzing the corresponding characteristic equations, we study the stabilities of equilibrium and the effect of delays on CTL immune response. The results indicate that when immune delay is present, the steady state of equilibrium is disrupted and leads to a Hopf bifurcation. Finally, we use sensitivity analyses to show the effect of parameters on thresholds and numerical simulations to illustrate the theoretical results. [ABSTRACT FROM AUTHOR]

Photothermal therapy (PTT) is a cancer-targeted treatment approach.The occurrence of tumors may be related to microbial infections (Viruses, bacteria, fungi, etc.), which probably provokes anti-tumor immunity. However, T cells in the context of cancer become exhausted and dysfunctional. Galectin-9 (Gal-9) is highly expressed in normal tissues and associates with body immune tolerance, and was firstly evidenced with much higher expression on the primary solid tumors than CD80/86 (B7) and CD274 (PD-L1) here, which suggests that Gal-9 may be a key factor in inhibiting the anti-tumor immunity, and its receptor T cell immunoglobulin and mucin domain 3 (TIM-3) was discovered on the cytotoxic T lymphocytes (CTL) with high expression as well based on the single cell analysis. The immune checkpoint communications showed that the Gal-9/TIM-3 axis played the most vital role on negatively regulating the anti-tumor immunity of CTL for melanoma. Then, we used a novel transdermal photothermal nanosensitizer (FSGG) loading Gal-9 siRNA (FSGG/siGal-9) for knocking the tumor cells down Gal-9 to block the Gal-9/TIM-3 axis and prohibit CTL exhaustion synergizing PTT against melanoma, which evidenced good effects on inhibiting tumor growth and enhancing anti-tumor immunity, named "photothermal immunotherapy". This paper provides a new perspective for tumor prevention and treatment. This study explores the synergistic effects of photothermal therapy and silencing Gal-9 to achieve photothermal immunotherapy treating melanoma with an integrated FSGG nanostructure. [ABSTRACT FROM AUTHOR]

Metastasis is one of the leading causes of cancer-related deaths. A comprehensive comparison of the differences between primary and metastatic cancers within the same organ can aid in understanding the growth mechanisms of cancer cells at metastatic sites, thereby helping to develop more effective targeted treatment strategies. Primary liver cancer is one of the most common types of cancer, and the liver is also one of the main metastatic sites. In this paper, we utilize single-cell RNA-Seq data to compare primary liver cancer and colorectal liver metastases from multiple perspectives, including cell types and proportions, activity of various cell types, cell–cell communication, mRNA expression differences within the same types of cells, key factors associated with cell proliferation, etc. Our analysis results show the following: (i) Compared to primary tissue, metastatic tissue contains more cytotoxic T cells and exhausted T cells, and it retains some specific characteristics of the primary site. (ii) Cells of the same type exhibit functional differences between primary and metastatic cancers, with metastatic cancer cells showing lower metabolism levels and immune cells exhibiting stronger immune activity. (iii) Interactions between monocytes and hepato-associated cells are strong in primary cancer, while depleted T cells frequently communicate with hepatocytes in metastatic cancer. (iv) Proliferation-related genes in primary and metastatic cancers are mainly involved in cell energy supply and basic metabolism activity, respectively. [ABSTRACT FROM AUTHOR]

Efforts to treat cancer using chimeric antigen receptor (CAR)-T therapy have made astonishing progress and clinical trials against hematopoietic malignancies have demonstrated their use. However, there are still disadvantages which need to be addressed: high costs, and side effects such as Graft-versus-Host Disease (GvHD) and Cytokine Release Syndrome (CRS). Therefore, recent efforts have been made to harness the properties of certain immune cells to treat cancer—not just T cells, but also natural killer (NK) cells, macrophages (Mφ), dendritic cells (DC), etc. In this paper, we will introduce immune cell-based cellular therapies that use various immune cells and describe their characteristics and their clinical situation. The development of immune cell-based cancer therapy fully utilizing the unique advantages of each and every immune cell is expected to enhance the survival of tumor patients owing to their high efficiency and fewer side effects. [ABSTRACT FROM AUTHOR]

Immunotherapy using immune checkpoint inhibitors (ICIs) has shown superior efficacy compared with conventional chemotherapy in certain cancer types, establishing immunotherapy as the fourth standard treatment alongside surgical intervention, chemotherapy, and radiotherapy. In cancer immunotherapy employing ICIs, CD8‐positive cytotoxic T lymphocytes are recognized as the primary effector cells. For effective clinical outcomes, it is essential that the targeted cancer cells express HLA class I molecules to present antigenic peptides derived from the tumor. However, cancer cells utilize various mechanisms to downregulate or lose HLA class I molecules from their surface, resulting in evasion from immune surveillance. Correlations between prognosis and the integrity of HLA class I molecules expressed by cancer cells have been consistently found across different types of cancer. This paper provides an overview of the regulatory mechanisms of HLA class I molecules and their role in cancer immunotherapy, with a particular emphasis on the significance of utilizing pathological tissues to evaluate HLA class I molecules expressed in cancer cells. [ABSTRACT FROM AUTHOR]

This paper develops a mathematical model to investigate the Human Immunodeficiency Virus (HIV) infection dynamics. The model includes two transmission modes (cell-to-cell and cell-free), two adaptive immune responses (cytotoxic T-lymphocyte (CTL) and antibody), a saturated CTL immune response, and latent HIV infection. The existence and local stability of equilibria are fully characterized by four reproduction numbers. Through sensitivity analyses, we assess the partial rank correlation coefficients of these reproduction numbers and identify that the infection rate via cell-to-cell transmission, the number of new viruses produced by each infected cell during its life cycle, the clearance rate of free virions, and immune parameters have the greatest impact on the reproduction numbers. Additionally, we compare the effects of immune stimulation and cell-to-cell spread on the model's dynamics. The findings highlight the significance of adaptive immune responses in increasing the population of uninfected cells and reducing the numbers of latent cells, infected cells, and viruses. Furthermore, cell-to-cell transmission is identified as a facilitator of HIV transmission. The analytical and numerical results presented in this study contribute to a better understanding of HIV dynamics and can potentially aid in improving HIV management strategies. [ABSTRACT FROM AUTHOR]

The article discusses the role of the tumor microenvironment (TME) in cancer development and progression. It highlights the various components of the TME, such as cancer cells, fibroblasts, immune cells, endothelial cells, adipocytes, and the extracellular matrix, and how they collectively influence cancer growth and resistance to therapy. The article also presents recent advances in therapeutic approaches that target the TME to treat metastatic tumors. It emphasizes the importance of understanding the interactions and metabolic adaptations within the TME to develop effective strategies for cancer patients. [Extracted from the article]

Breast cancer ranks among the most prevalent malignancies affecting the female population and is a prominent contributor to cancer-related mortality. Mathematical modeling is a significant tool that can be employed to comprehend the dynamics of breast cancer progression and dissemination and to formulate novel therapeutic approaches. This paper introduces a mathematical model of breast cancer that utilizes the Caputo–Fabrizio fractal-fractional derivative. The aim is to elucidate and comprehend the intricate dynamics governing breast cancer cells and cytotoxic T lymphocytes in the context of the fractional derivative. The derivative presented herein offers a broader perspective than the conventional derivative, as it incorporates the intricate fractal characteristics inherent in the process of tumor proliferation. The significance of this study lies in its contribution to a novel mathematical model for breast cancer, which incorporates the fractal characteristics of tumor development. The present model possesses the capability to investigate the impacts of diverse treatment strategies on the proliferation of breast cancer, as well as to formulate novel treatment strategies that exhibit enhanced efficacy. [ABSTRACT FROM AUTHOR]

In this paper, we study a model that enhances our understanding of cytokine-influenced HIV-1 infection. The impact of adaptive immune response (cytotoxic T lymphocytes (CTLs) and antibodies) and time delay on HIV-1 infection is included. The model takes into account two types of distributional delays, (i) the delay in the HIV-1 infection of CD4+T cells and (ii) the maturation delay of new virions. We first investigated the fundamental characteristics of the system, then found the system's equilibria. We derived five threshold parameters, ℜ i , i = 0, 1,..., 4, which completely determine the existence and stability of the equilibria. The Lyapunov method was used to prove the global asymptotic stability for all equilibria. We illustrate the theoretical results by performing numerical simulations. We also performed a sensitivity analysis on the basic reproduction number ℜ 0 and identified the most-sensitive parameters. We found that pyroptosis contributes to the number ℜ 0 , and then, neglecting it will make ℜ 0 underevaluated. Necrosulfonamide and highly active antiretroviral drug therapy (HAART) can be effective in preventing pyroptosis and at reducing viral replication. Further, it was also found that increasing time delays can effectively decrease ℜ 0 and, then, inhibit HIV-1 replication. Furthermore, it is shown that both CTLs and antibody immune responses have no effect on ℜ 0 , while this can result in less HIV-1 infection. [ABSTRACT FROM AUTHOR]

This paper formulates and analyzes two mathematical models that describe the within-host dynamics of human immunodeficiency virus type 1 (HIV-1) with impairment of both cytotoxic T lymphocytes (CTLs) and B cells. Both viral transmission (VT) and cellular infection (CT) mechanisms are considered. The second model is a generalization of the first model that includes distributed time delays. For the two models, we establish the non-negativity and boundedness of the solutions, find the basic reproductive numbers, determine all possible steady states and establish the global asymptotic stability properties of all steady states by means of the Lyapunov method. We confirm the theoretical results by conducting numerical simulations. We conduct a sensitivity analysis to show the effect of the values of the parameters on the basic reproductive number. We discuss the results, showing that impaired B cells and CTLs, time delay and latent CT have significant effects on the HIV-1 dynamics. [ABSTRACT FROM AUTHOR]

This paper presents and analyzes two mathematical models for the human immunodeficiency virus type-1 (HIV-1) infection with Cytotoxic T Lymphocyte cell (CTL) immune impairment. These models describe the interactions between healthy CD 4 + T cells, latently and actively infected cells, HIV-1 particles, and CTLs. The healthy CD 4 + T cells might be infected when they make contact with: (i) HIV-1 particles due to virus-to-cell (VTC) contact; (ii) latently infected cells due to latent cell-to-cell (CTC) contact; and (iii) actively infected cells due to active CTC contact. Distributed time delays are considered in the second model. We show the nonnegativity and boundedness of the solutions of the systems. Further, we derive basic reproduction numbers ℜ 0 and ℜ ˜ 0 , that determine the existence and stability of equilibria of our proposed systems. We establish the global asymptotic stability of all equilibria by using the Lyapunov method together with LaSalle's invariance principle. We confirm the theoretical results by numerical simulations. The effect of immune impairment, time delay and CTC transmission on the HIV-1 dynamics are discussed. It is found that weak immunity contributes significantly to the development of the disease. Further, we have established that the presence of time delay can significantly decrease the basic reproduction number and then suppress the HIV-1 replication. On the other hand, the presence of latent CTC spread increases the basic reproduction number and then enhances the viral progression. Thus, neglecting the latent CTC spread in the HIV-1 infection model will lead to an underestimation of the basic reproduction number. Consequently, the designed drug therapies will not be accurate or sufficient to eradicate the viruses from the body. These findings may help to improve the understanding of the dynamics of HIV-1 within a host. [ABSTRACT FROM AUTHOR]

This document is a first-person interview with Fabrizia Zevolini, the first author of a paper titled "Polo-like kinase 1 regulates immune synapse assembly and cytotoxic T cell function by driving microtubule dynamics." The paper discusses the role of Polo-like kinase 1 (PLK1) in the assembly of the immune synapse, a cell-cell contact that cytotoxic T cells establish with their targets for effective killing. The study found that inhibiting PLK1 suppressed cytotoxic T cell function, highlighting a potential drawback of PLK1-targeted therapies. The author also discusses the challenges faced during the project and their motivation to pursue a career in science. The paper was published in the Journal of Cell Science, a prestigious journal that reaches a broad scientific community. [Extracted from the article]

The intratumor microbiome imbalance in pancreatic cancer promotes a tolerogenic immune response and triggers immunotherapy resistance. Here we show that Lactobacillus rhamnosus GG probiotics, outfitted with a gallium-polyphenol network (LGG@Ga-poly), bolster immunotherapy in pancreatic cancer by modulating microbiota-immune interactions. Upon oral administration, LGG@Ga-poly targets pancreatic tumors specifically, and selectively eradicates tumor-promoting Proteobacteria and microbiota-derived lipopolysaccharides through a gallium-facilitated disruption of bacterial iron respiration. This elimination of intratumor microbiota impedes the activation of tumoral Toll-like receptors, thus reducing immunosuppressive PD-L1 and interleukin-1β expression by tumor cells, diminishing immunotolerant myeloid populations, and improving the infiltration of cytotoxic T lymphocytes in tumors. Moreover, LGG@Ga-poly hampers pancreatic tumor growth in both preventive and therapeutic contexts, and amplifies the antitumor efficacy of immune checkpoint blockade in preclinical cancer models in female mice. Overall, we offer evidence that thoughtfully designed biomaterials targeting intratumor microbiota can efficaciously augment immunotherapy for the challenging pancreatic cancer. The intratumor microbiota in pancreatic cancer has been described as pro-tumorigenic. Here the authors modify the probiotic Lactobacillus rhamnosus GG with a gallium-polyphenol network and chitosan nanocoating, showing accumulation in pancreatic lesions and modulation of the intratumor microbiota, eliciting anti-tumor immune response in preclinical models. [ABSTRACT FROM AUTHOR]

Compensation and intracellular storage of PD-L1 may compromise the efficacy of antibody drugs targeting the conformational blockade of PD1/PD-L1 on the cell surface. Alternative therapies aiming to reduce the overall cellular abundance of PD-L1 thus might overcome resistance to conventional immune checkpoint blockade. Here we show by bioinformatics analysis that colon adenocarcinoma (COAD) with high microsatellite instability (MSI-H) presents the most promising potential for this therapeutic intervention, and that overall PD-L1 abundance could be controlled via HSC70-mediated lysosomal degradation. Proteomic and metabolomic analyses of mice COAD with MSI-H in situ unveil a prominent acidic tumor microenvironment. To harness these properties, an artificial protein, IgP β, is engineered using pH-responsive peptidic foldamers. This features customized peptide patterns and designed molecular function to facilitate interaction between neoplastic PD-L1 and HSC70. IgP β effectively reduces neoplastic PD-L1 levels via HSC70-mediated lysosomal degradation, thereby persistently revitalizing the action of tumor-infiltrating CD8 + T cells. Notably, the anti-tumor effect of lysosomal-degradation-based therapy surpasses that of antibody-based immune checkpoint blockade for MSI-H COAD in multiple mouse models. The presented strategy expands the use of peptidic foldamers in discovering artificial protein drugs for targeted cancer immunotherapy. The efficiency of antibody-based immune checkpoint blockades could be compromised by the intracellular accumulation of checkpoint proteins. Here authors show that a pH-responsive artificial protein that targets PD-L1 to lysosomal degradation could achieve superior therapeutic effect compared to anti-PD-L1 treatment in mouse models of high microsatellite instability colon adenocarcinoma. [ABSTRACT FROM AUTHOR]

The combination of radiotherapy/chemoradiotherapy and immune checkpoint blockade can result in poor outcomes in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Here, we show that combining ATR inhibition (ATRi) with radiotherapy (RT) increases the frequency of activated NKG2A+PD-1+ T cells in animal models of HNSCC. Compared with the ATRi/RT treatment regimen alone, the addition of simultaneous NKG2A and PD-L1 blockade to ATRi/RT, in the adjuvant, post-radiotherapy setting induces a robust antitumour response driven by higher infiltration and activation of cytotoxic T cells in the tumour microenvironment. The efficacy of this combination relies on CD40/CD40L costimulation and infiltration of activated, proliferating memory CD8+ and CD4+ T cells with persistent or new T cell receptor (TCR) signalling, respectively. We also observe increased richness in the TCR repertoire and emergence of numerous and large TCR clonotypes that cluster based on antigen specificity in response to NKG2A/PD-L1/ATRi/RT. Collectively, our data point towards potential combination approaches for the treatment of HNSCC. Immune checkpoint blockade can result in good outcomes in patients with metastatic head and neck squamous cell carcinoma (HNSCC), but not those with locally advanced disease. Here, the authors demonstrate that the addition of anti-NKG2A and anti-PD-L1 blockade to ATR inhibition and radiotherapy in the adjuvant setting can induce a robust antitumour immune response in mice. [ABSTRACT FROM AUTHOR]

We previously demonstrated that glycyrrhizin (GL) suppressed inflammation and carcinogenesis in an azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced murine model of colorectal cancer (CC). In this study, we found an accumulation of regulatory T cells (Tregs) in the spleen and suppression by GL in model mice. ICR mice were divided into four groups: Control, GL, CC, and GL-treated CC (CC+GL), and were sacrificed 20 weeks after AOM/DSS treatment. We measured spleen weight, areas of white and red pulp, and CD8+ T cells (cytotoxic T lymphocytes, CTL), and CD11c-positive cells (dendritic cells) in splenic tissues and forkhead box protein 3 (FoxP3)-positive cells (Tregs) in colorectal and splenic tissues. In all cases, the CC group showed a significant increase compared with those in Control group, and GL administration significantly attenuated this increase. These results indicate that Tregs accumulated in the spleen may participate in inflammation-related carcinogenesis by suppressing CTL. We also suggest that GL which binds to high-mobility group box 1 (HMGB1), suppresses carcinogenesis with decreasing Tregs in the spleen. Furthermore, there was an expression of FoxP3 in cancer cells, indicating that it may be involved in the malignant transformation of cancer cells. [ABSTRACT FROM AUTHOR]

The immunosuppressive tumor microenvironment (TME) has become a major challenge in cancer immunotherapy, with abundant tumor-associated macrophages (TAMs) playing a key role in promoting tumor immune escape by displaying an immunosuppressive (M2) phenotype. Recently, it was reported that M1 macrophage-derived nanovesicles (M1NVs) can reprogram TAMs to an anti-tumor M1 phenotype, thereby significantly alleviating the immunosuppressive TME and enhancing the anti-tumor efficacy of immunotherapy. Herein, we developed M1NVs loaded with mesoporous dopamine (MPDA) and indocyanine green (ICG), which facilitated the recruitment of M2 TAMs through synergistic photothermal and photodynamic therapy. Thereafter, M1NVs can induce M1 repolarization of TAMs, resulting in increased infiltration of cytotoxic T lymphocytes within the tumor to promote tumor regression. This study investigated the effect of phototherapy on the immune environment of liver cancer using single-cell RNA sequencing (scRNA-seq) by comparing HCC tissues before and after MPDA/ICG@M1NVs + NIR treatment. The results showed significant shifts in cell composition and gene expression, with decreases in epithelial cells, B cells, and macrophages and increases in neutrophils and myeloid cells. Additionally, gene analysis indicated a reduction in pro-inflammatory signals and immunosuppressive functions, along with enhanced B-cell function and anti-tumor immunity, downregulation of the Gtsf1 gene in the epithelial cells of the MPDA/ICG @M1NVs + NIR group, and decreased expression of the lars2 gene in immune subpopulations. Eno3 expression is reduced in M1 macrophages, whereas Clec4a3 expression is downregulated in M2 macrophages. Notably, the B cell population decreased, whereas Pou2f2 expression increased. These genes regulate cell growth, death, metabolism, and tumor environment, indicating their key role in HCC progression. This study highlights the potential for understanding cellular and molecular dynamics to improve immunotherapy. [ABSTRACT FROM AUTHOR]

Compensation and intracellular storage of PD-L1 may compromise the efficacy of antibody drugs targeting the conformational blockade of PD1/PD-L1 on the cell surface. Alternative therapies aiming to reduce the overall cellular abundance of PD-L1 thus might overcome resistance to conventional immune checkpoint blockade. Here we show by bioinformatics analysis that colon adenocarcinoma (COAD) with high microsatellite instability (MSI-H) presents the most promising potential for this therapeutic intervention, and that overall PD-L1 abundance could be controlled via HSC70-mediated lysosomal degradation. Proteomic and metabolomic analyses of mice COAD with MSI-H in situ unveil a prominent acidic tumor microenvironment. To harness these properties, an artificial protein, IgP β, is engineered using pH-responsive peptidic foldamers. This features customized peptide patterns and designed molecular function to facilitate interaction between neoplastic PD-L1 and HSC70. IgP β effectively reduces neoplastic PD-L1 levels via HSC70-mediated lysosomal degradation, thereby persistently revitalizing the action of tumor-infiltrating CD8 + T cells. Notably, the anti-tumor effect of lysosomal-degradation-based therapy surpasses that of antibody-based immune checkpoint blockade for MSI-H COAD in multiple mouse models. The presented strategy expands the use of peptidic foldamers in discovering artificial protein drugs for targeted cancer immunotherapy. The efficiency of antibody-based immune checkpoint blockades could be compromised by the intracellular accumulation of checkpoint proteins. Here authors show that a pH-responsive artificial protein that targets PD-L1 to lysosomal degradation could achieve superior therapeutic effect compared to anti-PD-L1 treatment in mouse models of high microsatellite instability colon adenocarcinoma. [ABSTRACT FROM AUTHOR]

The combination of radiotherapy/chemoradiotherapy and immune checkpoint blockade can result in poor outcomes in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Here, we show that combining ATR inhibition (ATRi) with radiotherapy (RT) increases the frequency of activated NKG2A+PD-1+ T cells in animal models of HNSCC. Compared with the ATRi/RT treatment regimen alone, the addition of simultaneous NKG2A and PD-L1 blockade to ATRi/RT, in the adjuvant, post-radiotherapy setting induces a robust antitumour response driven by higher infiltration and activation of cytotoxic T cells in the tumour microenvironment. The efficacy of this combination relies on CD40/CD40L costimulation and infiltration of activated, proliferating memory CD8+ and CD4+ T cells with persistent or new T cell receptor (TCR) signalling, respectively. We also observe increased richness in the TCR repertoire and emergence of numerous and large TCR clonotypes that cluster based on antigen specificity in response to NKG2A/PD-L1/ATRi/RT. Collectively, our data point towards potential combination approaches for the treatment of HNSCC. Immune checkpoint blockade can result in good outcomes in patients with metastatic head and neck squamous cell carcinoma (HNSCC), but not those with locally advanced disease. Here, the authors demonstrate that the addition of anti-NKG2A and anti-PD-L1 blockade to ATR inhibition and radiotherapy in the adjuvant setting can induce a robust antitumour immune response in mice. [ABSTRACT FROM AUTHOR]

Background: TLR7 is a key player in the antiviral immunity. TLR7 signaling activates antigen-presenting cells including DCs and macrophages. This activation results in the adaptive immunity including T cells and B cells. Therefore, TLR7 is an important molecule of the immune system. Based on these observations, TLR7 agonists considered to become a therapy weaponize the immune system against cancer. Radiation therapy (RT) is one of the standard cancer therapies and is reported to modulate the tumor immune response. In this study, we aimed to investigate the anti-tumor activity in combination of TLR7 agonist, DSP-0509, with RT and underlying mechanism. Result: We showed that anti-tumor activity is enhanced by combining RT with the TLR7 agonist DSP-0509 in the CT26, LM8, and 4T1 inoculated mice models. We found that once- weekly (q1w) dosing of DSP-0509 rather than biweekly (q2w) dosing is needed to achieve superior anti-tumor activities in CT26 model. Spleen cells from the mice in RT/DSP-0509 combination treatment group showed increased tumor lytic activity, inversely correlated with tumor volume, as measured by the chromium-release cytotoxicity assay. We also found the level of cytotoxic T lymphocytes (CTLs) increased in the spleens of completely cured mice. When the mice completely cured by combination therapy were re-challenged with CT26 cells, all mice rejected CT26 cells but accepted Renca cells. This rejection was not observed with CD8 depletion. Furthermore, levels of splenic effector memory CD8 T cells were increased in the combination therapy group. To explore the factors responsible for complete cure by combination therapy, we analyzed peripheral blood leukocytes (PBLs) mRNA from completely cured mice. We found that Havcr2low, Cd274low, Cd80high, and Il6low were a predictive signature for the complete response to combination therapy. An analysis of tumor-derived mRNA showed that combination of RT and DSP-0509 strongly increased the expression of anti-tumor effector molecules including Gzmb and Il12. Conclusion: These data suggest that TLR7 agonist, DSP-0509, can be a promising concomitant when used in combination with RT by upregulating CTLs activity and gene expression of effector molecules. This combination can be an expecting new radio-immunotherapeutic strategy in clinical trials. [ABSTRACT FROM AUTHOR]

Abnormalities in glucose metabolism that precede the onset of type 2 diabetes (T2D) activate immune cells, leading to elevated inflammatory factors and chronic inflammation. However, no single-cell RNA sequencing (scRNA-seq) studies have characterized the properties and networks of individual immune cells in T2D. Here, we analyzed peripheral blood mononuclear cells (PBMCs) from non-diabetes and T2D patients by scRNA-seq. We found that CD14 monocytes in T2D patients were in a pro-inflammatory state and intermediate monocytes expressed more MHC class II genes. In T2D patients, cytotoxic CD4 T cells, effector memory CD8 T cells, and gd T cells have increased cytotoxicity and clonal expansion. B cells were characterized by increased differentiation into intermediate B cells, plasma cells, and isotype class switching with increased expression of soluble antibody genes. These results suggest that monocytes, T cells, and B cells could interact to induce chronic inflammation in T2D patients with pro-inflammatory characteristics. [ABSTRACT FROM AUTHOR]

Elevated levels of miR-155 in solid and liquid malignancies correlate with aggressiveness of the disease. In this manuscript, we show that miR-155 targets transcripts encoding IcosL, the ligand for Inducible T-cell costimulator (Icos), thus impairing the ability of T cells to recognize and eliminate malignant cells. We specifically found that overexpression of miR-155 in B cells of Eµ-miR-155 mice causes loss of IcosL expression as they progress toward malignancy. Similarly, in mice where miR-155 expression is controlled by a Cre-Tet-OFF system, miR-155 induction led to malignant infiltrates lacking IcosL expression. Conversely, turning miR-155 OFF led to tumor regression and emergence of infiltrates composed of IcosL-positive B cells and Icos-positive T cells forming immunological synapses. Therefore, we next engineered malignant cells to express IcosL, in order to determine whether IcosL expression would increase tumor infiltration by cytotoxic T cells and reduce tumor progression. Indeed, overexpressing an IcosL-encoding cDNA in MC38 murine colon cancer cells before injection into syngeneic C57BL6 mice reduced tumor size and increased intratumor CD8+ T cell infiltration, that formed synapses with IcosL-expressing MC38 cells. Our results underscore the fact that by targeting IcosL transcripts, miR-155 impairs the infiltration of tumors by cytotoxic T cells, as well as the importance of IcosL on enhancing the immune response against malignant cells. These findings should lead to the development of more effective anticancer treatments based on maintaining, increasing, or restoring IcosL expression by malignant cells, along with impairing miR-155 activity. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) remains a global public health threat. Understanding the dynamics of host-pathogen interactions within TB granulomas will assist in identifying what leads to the successful elimination of infection. In vitro TB models provide a controllable environment to study these granuloma dynamics. Previously we developed a biomimetic 3D spheroid granuloma model that controls bacteria better than a traditional monolayer culture counterpart. We used agent-based simulations to predict the mechanistic reason for this difference. Our calibrated simulations were able to predict heterogeneous bacterial dynamics that are consistent with experimental data. In one group of simulations, spheroids are found to have higher macrophage activation than their traditional counterparts, leading to better bacterial control. This higher macrophage activation in the spheroids was not due to higher counts of activated T cells, instead fewer activated T cells were able to activate more macrophages due to the proximity of these cells to each other within the spheroid. In a second group of simulations, spheroids again have more macrophage activation but also more T cell activation, specifically CD8+ T cells. This higher level of CD8+ T cell activation is predicted to be due to the proximity of these cells to the cells that activate them. Multiple mechanisms of control were predicted. Simulations removing individual mechanisms show that one group of simulations has a CD4+ T cell dominant response, while the other has a mixed/CD8+ T cell dominant response. Lastly, we demonstrated that in spheroids the initial structure and movement rules work synergistically to reduce bacterial load. These findings provide valuable insights into how the structural complexity of in vitro models impacts immune responses. Moreover, our study has implications for engineering more physiologically relevant in vitro models and advancing our understanding of TB pathogenesis and potential therapeutic interventions. Author summary: Tuberculosis (TB) is a respiratory infection that is associated with granulomas, organized clusters of immune cells that form around the bacteria. Recent work has focused on making in vitro models that better approximate these granulomas, such as our spheroid granuloma model. We found that this spheroid was better able to control bacteria than its traditional culture counterpart, so, in this work, we use agent-based modeling to explore the causes of this differential control. The simulated spheroids have increased macrophage activation. Surprisingly, this is not due to larger numbers of activated T cells, which activate these macrophages. Rather, the increase in activated macrophages is due to their proximity to fewer activated T cells. We also see a subset of simulations where the spheroids have increased cytotoxic CD8+ T cell activation. The simulation is further used to simulate changes in the structure of the in vitro models to explore its impact on immune response and bacterial control. These findings reveal the importance of structural complexity in in vitro models and offer insights into TB pathogenesis. Ultimately, our work paves the way for more realistic in vitro models and a deeper understanding of how our bodies combat TB. [ABSTRACT FROM AUTHOR]

Background: The involvement of cytotoxic CD4+ T cells (CD4+ CTLs) and their potential role in dictating the response to immune checkpoint inhibitors (ICIs) in patients with metastatic renal cell carcinoma (mRCC) remains an unexplored area of research. Methods: Utilizing single-cell RNA sequencing, we analyzed the immunophenotype and expression patterns of CD4+ T lymphocyte subtypes in mRCC patients, followed by preliminary validation via multi-immunofluorescent staining. In addition, we obtained a comprehensive immunotherapy dataset encompassing single-cell RNA sequencing datasets and bulk RNA-seq cohorts from the European Genome-Phenome Archive and ArrayExpress database. Utilizing the CIBERSORTx deconvolution algorithms, we derived a signature score for CD4+ CTLs from the bulk-RNA-seq datasets of the CheckMate 009/025 clinical trials. Results: Single-cell analysis of CD4+ T lymphocytes in mRCC reveals several cancer-specific states, including diverse phenotypes of regulatory T cells. Remarkably, we observe that CD4+ CTLs cells constitute a substantial proportion of all CD4+ T lymphocyte sub-clusters in mRCC patients, highlighting their potential significance in the disease. Furthermore, within mRCC patients, we identify two distinct cytotoxic states of CD4+ T cells: CD4+GZMK+ T cells, which exhibit a weaker cytotoxic potential, and CD4+GZMB+ T cells, which demonstrate robust cytotoxic activity. Both regulatory T cells and CD4+ CTLs originate from proliferating CD4+ T cells within mRCC tissues. Intriguingly, our trajectory analysis indicates that the weakly cytotoxic CD4+GZMK+ T cells differentiate from their more cytotoxic CD4+GZMB+ counterparts. In comparing patients with lower CD4+ CTLs levels to those with higher CD4+ CTLs abundance in the CheckMate 009 and 25 immunotherapy cohorts, the latter group exhibited significantly improved OS and PFS probability. Conclusion: Our study underscores the pivotal role that intratumoral CD4+ CTLs may play in bolstering anti-tumor immunity, suggesting their potential as a promising biomarker for predicting response to ICIs in patients with mRCC. [ABSTRACT FROM AUTHOR]

Background. Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer, and while advancements in diagnosis, surgery, radiotherapy, and molecular therapy have improved clinical prognosis, the long-term survival rate and quality of life of patients remain unsatisfactory. Therefore, identifying new prognostic biomarkers and potential therapeutic targets is crucial. Objectives. This study aimed to analyze the role of anoikis-related gene characteristics in LUAD. Materials and methods. The anoikis-related genes were obtained from the GeneCards database. Genetic expression data and clinical characteristic information were collected from The Cancer Genome Atlas (TCGA)-LUAD, and the Gene Expression Omnibus (GEO) GSE31210, GSE37745, and GSE68465 datasets. Random survival forest and least absolute shrinkage and selection operator (LASSO) models were applied to construct the risk model. An analysis of immune cell infiltration and function was performed with the scores. Results. Four prognosis-related genes (TLE1, GLI2, PLK1, and BAK1) were obtained and used to construct the anoikis score. We found that the patient survival rate was higher in the low-anoikis score (LAS) group. Moreover, both the stromal and immune scores were negatively correlated with the anoikis score. With the increase of the anoikis score, the levels of natural killer cells, regulatory T cells, CD4+ T cells, CD8+ T cells, B cells, and macrophages decreased. The anoikis score had a negative regulatory relationship with the immune response, natural killer cell activation and T cell activation. The TP53 mutation was significant in LUAD patients and was present in 56% of the high-anoikis score (HAS) group and in 40% of the LAS group. Conclusions. The anoikis score was associated with poor prognosis in LUAD patients. Anoikis-related genes were associated with tumor immune dysregulation and TP53 mutation in LUAD. This study opens a new perspective for LUAD therapy. [ABSTRACT FROM AUTHOR]

Obesity is a multifactorial disease associated with low-grade inflammation. The gut is thought to be involved in obesity-related inflammation, as it is continuously exposed to antigens from food, microbiota and metabolites. However, the exact underlying mechanisms are still unknown. Therefore, we examined the relation between gut pathology, microbiota, its metabolites and cytokines in adults with severe obesity. Individuals eligible for bariatric surgery were included. Fecal and plasma samples were collected at surgery timepoint, to assess microbiota and metabolite composition. Jejunal biopsies were collected during surgery and stained for cytotoxic T cells, macrophages, mast cells and tight junction component zonula occludens-1. Based on these stainings, the cohort was divided into four groups: high versus low intestinal inflammation and high versus low intestinal integrity. We found no significant differences in microbiota diversity between groups, nor for individual bacterial species. No significant differences in metabolites were observed between the intestinal inflammatory groups. However, some metabolites and cytokines differed between the intestinal integrity groups. Higher plasma levels of interleukin-8 and tauro-chenodeoxycholic acid were found, whereas isovaleric acid and acetic acid were lower in the high intestinal integrity group. As the results were very subtle, we suggest that our cohort shows very early and minor intestinal pathology. [ABSTRACT FROM AUTHOR]

Post-transplant cyclophosphamide (PTCy) is becoming the standard prophylaxis for graft-versus-host disease (GVHD) in HLA-haploidentical allogeneic hematopoietic cell transplantation (allo-HCT) and in HLA-matched allo-HCT. Immune reconstitution in the post-transplant setting may influence the graftversus- tumor (GVT) effect because PTCy has a profound effect on T cell and natural killer cell functions and their reconstitution after allo-HCT. However, many recent studies have shown that the incidence of relapse after allo-HCT with PTCy is comparable to that after conventional allo-HCT. To further improve the outcomes, it is critical to establish a strategy to maintain or effectively induce the GVT effect when using PTCy as a platform for GVHD prophylaxis. However, there is a paucity of studies focusing on the GVT effect in allo-HCT with PTCy. Therefore, focusing on this issue may lead to the establishment of more appropriate strategies to improve transplantation outcomes without exacerbating GVHD, including novel therapies involving cell modification. [ABSTRACT FROM AUTHOR]

Chemotherapy and immunotherapy have shown no significant outcome for unresectable pancreatic ductal adenocarcinoma (PDAC). Multi-drug combination therapy has become a consensus in clinical trials to explore how to arouse anti-tumor immunity and meanwhile overcome the poorly tumoricidal effect and the stroma barrier that greatly hinders drug penetration. To address this challenge, a comprehensive strategy is proposed to fully utilize both the ferroptotic vulnerability of PDAC to potently irritate anti-tumor immunity and the desmoplasia-associated focal adhesion kinase (FAK) to wholly improve the immunosuppressive microenvironment via sustained release of drugs in an injectable hydrogel for increasing drug penetration in tumor location and averting systematic toxicity. The injectable hydrogel ED-M@CS/MC is hybridized with micelles loaded with erastin that exclusively induces ferroptosis and a FAK inhibitor defactinib for inhibiting stroma formation, and achieves sustained release of the drugs for up to 12 days. With only a single intratumoral injection, the combination treatment with erastin and defactinib produces further anti-tumor performance both in xenograft and KrasG12D-engineered primary PDAC mice and synergistically promotes the infiltration of CD8+ cytotoxic T cells and the reduction of type II macrophages. The findings may provide a novel promising strategy for the clinical treatment of PDAC. [ABSTRACT FROM AUTHOR]

Immune cells have intensely physical lifestyles characterized by structural plasticity and force exertion. To investigate whether specific immune functions require stereotyped mechanical outputs, we used super-resolution traction force microscopy to compare the immune synapses formed by cytotoxic T cells with contacts formed by other T cell subsets and by macrophages. T cell synapses were globally compressive, which was fundamentally different from the pulling and pinching associated with macrophage phagocytosis. Spectral decomposition of force exertion patterns from each cell type linked cytotoxicity to compressive strength, local protrusiveness, and the induction of complex, asymmetric topography. These features were validated as cytotoxic drivers by genetic disruption of cytoskeletal regulators, live imaging of synaptic secretion, and in silico analysis of interfacial distortion. Synapse architecture and force exertion were sensitive to target stiffness and size, suggesting that the mechanical potentiation of killing is biophysically adaptive. We conclude that cellular cytotoxicity and, by implication, other effector responses are supported by specialized patterns of efferent force. Editor's summary: Immune cells apply mechanical forces to their surrounding environment, but whether their biomechanical output is tuned to support distinct immunological functions remains unclear. Using super-resolution traction force microscopy, de Jesus et al. compared the patterns of interfacial forces exerted by cytotoxic T lymphocytes (CTLs) with other immune cells. Within the immune synapse, CTLs formed a complex compressive crater, a biomechanical signature that was distinct from those of macrophages initiating phagocytosis and T cells engaging in nonlytic interactions. These findings demonstrate that immune cells exert specialized patterns of force on their targets to carry out distinct immunological functions. —Claire Olingy [ABSTRACT FROM AUTHOR]

Simple Summary: A widely used test to establish if a person has T-cells that react against an infection or against a cancer is the enzyme-linked ImmunoSpot (ELISPOT assay). The person's T-cells are mixed with short lengths of amino acids called peptides that span the protein targets (antigens) step-wise in an overlapping manner, in order to stimulate a measurable response in the form of countable spots on the membrane of the ELISPOT plate, which indicate cytokine secretion by individual T cells. Whilst research has shown that responsive peptides for certain individuals can be predicted by computer programs, we show that using large peptide pools representing several antigens reveal most effectively the majority of the T cell reactivity against viruses. Such an approach is also likely to be most effective in cancers. Synthetic peptides derived from antigen sequences are essential reagents for the detection of CD8+ cytotoxic T lymphocytes (CTLs), in assays such as ELISPOT/ImmunoSpot®. Indeed, the combination of peptides and ImmunoSpot® has been widely used for immune monitoring in numerous vaccine trials. Target antigens in pathogens or cancers may be large in size and multiple in number, often seemingly necessitating in silico peptide epitope predictions using algorithms and programs for certain HLA alleles to narrow down the numbers of required peptides. In this commentary, we discuss our data in the context of immune responses to viral and cancer antigens, concluding that systematic high-throughput immune monitoring of CD8+ T cells will provide more reliable insights on the host's response to cancer than the reliance on select CD8+ T cell epitopes, no matter whether these are in silico predicted or even if they had been empirically established. We show the feasibility of large scale, high-throughput systematic CD8+ T cell epitope testing towards this goal. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive cancer with striking fibrosis, and its mortality rate is ranked second across human cancers. Cancer-associated fibroblasts (CAFs) play a critical role in PDAC progression, and we reviewed the molecular understanding of PDAC CAFs and novel therapeutic potential at present. CAFs-associated genes (CAFGs) were tentatively classified into three categories by stroma specificity representing stroma/epithelia expression ratios (SE ratios). The recent classification using single cell transcriptome technology clarified that CAFs were composed of myofibroblasts (myCAFs), inflammatory CAFs (iCAFs), and other minor ones (e.g., POSTN-CAFs and antigen presenting CAFs, apCAFs). LRRC15 is a myCAFs marker, and myCAFs depletion by diphtheria toxin induces the rapid accumulation of cytotoxic T lymphocytes (CTLs) and therefore augment PDL1 antibody treatments. This finding proposes that myCAFs may be a critical regulator of tumor immunity in terms of PDAC progression. myCAFs are located in CAFs adjacent to tumor cells, while iCAFs marked by PDPN and/or COL14A1 are distant from tumor cells, where hypoxic and acidic environments being located in iCAFs putatively due to poor blood supply is consistent with HIF1A and GPR68 expressions. iCAFs may be shared with SASP (secretion-associated phenotypes) in senescent CAFs. myCAFs are classically characterized by CAFGs induced by TGFB1, while chemoresistant CAFs with SASP may dependent on IL6 expression and accompanied by STAT3 activation. Recently, it was found that the unique metabolism of CAFs can be targeted to prevent PDAC progression, where PDAC cells utilize glucose, whereas CAFs in turn utilize lactate, which may be epigenetically regulated, mediated by its target genes including CXCR4. In summary, CAFs have unique molecular characteristics, which have been rigorously clarified as novel therapeutic targets of PDAC progression. [ABSTRACT FROM AUTHOR]

This paper is devoted to proposing a mathematical model in order to explore the dynamics of HTLV-Ⅰ (human T-cell leukemia virus type-Ⅰ) infection, in which the closely related target cell-virus-immune system interaction and the time-delay cytotoxic T lymphocyte (CTL) immune response are taken into consideration. Firstly, we give the relevant lemma for the existence of feasible equilibrium points of the model, and then further certify the global asymptotic stabilities of the infection-free equilibrium (IFFE) $ E_1 $ and the immune-free equilibrium (IMFE) $ E_2 $. Furthermore, we research the existence of Hopf bifurcation (HB) occurring at the immune equilibrium (IE) $ E^* $ due to the influence of the delay bifurcation parameter. Also, the numerical simulations confirm this fact. In addition, we obtain the explicit expressions which determine the direction and stability of HB. Finally, a succinct discussion shows that the delay in CTL response can destabilize $ E^* $ and generate HB, but not affect stabilities of $ E_1 $ and $ E_2 $. [ABSTRACT FROM AUTHOR]

Tumor immune escape refers to the inability of the immune system to clear tumor cells, which is one of the major obstacles in designing effective treatment schemes for cancer diseases. Although clinical studies have led to promising treatment outcomes, it is imperative to design theoretical models to investigate the long-term treatment effects. In this paper, we develop a mathematical model to study the interactions among tumor cells, immune escape tumor cells, and T lymphocyte. The chimeric antigen receptor (CAR) T-cell therapy is also described by the mathematical model. Bifurcation analysis shows that there exists backward bifurcation and saddle-node bifurcation when the immune intensity is used as the bifurcation parameter. The proposed model also exhibits bistability when its parameters are located between the saddle-node threshold and backward bifurcation threshold. Sensitivity analysis is performed to illustrate the effects of different mechanisms on the backward bifurcation threshold and basic immune reproduction number. Simulation studies confirm the bifurcation analysis results and predict various types of treatment outcomes using different CAR T-cell therapy strengths. Analysis and simulation results show that the immune intensity can be used to control the tumor size, but it has no effect on the control of the immune escape tumor size. The introduction of the CAR T-cell therapy will reduce the immune escape tumor size and the treatment effect depends on the CAR T-cell therapy strength. [ABSTRACT FROM AUTHOR]

Simple Summary: Cell therapy is emerging as a promising modality to treat cancers such as hematological malignancies and solid tumors; hence there is a need to develop processes to manufacture and maintain functional and lasting cells. The use of cytokines, as well as transcription and growth factors, is critical to ensure effective cell therapeutics. This is especially important for allogeneic cell therapies that employ induced pluripotent stem cells (iPSC). The use of iPSC offers the potential to treat a large number of patients with consistent material without relying on limited donor cells and the delay associated with processing immediately before treatment. This paper demonstrates the importance and use of cytokines and growth factors in driving the iPSC-to-effector differentiation and expansion process, which leads to the generation of functional and persistent immune-effector cells such as natural killer cells or T cells. Cytokines and other growth factors are essential for cell expansion, health, function, and immune stimulation. Stem cells have the additional reliance on these factors to direct differentiation to the appropriate terminal cell type. Successful manufacturing of allogeneic cell therapies from induced pluripotent stem cells (iPSCs) requires close attention to the selection and control of cytokines and factors used throughout the manufacturing process, as well as after administration to the patient. This paper employs iPSC-derived natural killer cell/T cell therapeutics to illustrate the use of cytokines, growth factors, and transcription factors at different stages of the manufacturing process, ranging from the generation of iPSCs to controlling of iPSC differentiation into immune-effector cells through the support of cell therapy after patient administration. [ABSTRACT FROM AUTHOR]

In this paper, a reaction–diffusion–chemotaxis HIV-1 model with a cytotoxic T lymphocyte (CTL) immune response and general sensitivity is investigated. We first prove the global classical solvability and L ∞ -boundedness for the considered model in a bounded domain with arbitrary spatial dimensions, which extends the previous existing results. Then, we apply the global existence result to the case with a linear proliferation immune response and an incidence rate. We study the spatiotemporal dynamics about the three types of spatially homogeneous steady states: infection-free steady state S 0 , CTL-inactivated infection steady state S 1 , and CTL-activated infection steady state S ∗. Our analyses indicate that S 0 is globally asymptotically stable if the basic reproduction number R 0 is less than 1; if R 0 is between 1 and a threshold, then S 1 is globally asymptotically stable. However, if R 0 is larger than the threshold, then the chemoattraction and chemorepulsion can destabilize S ∗ , and thus, a spatiotemporal pattern forms as the chemotactic sensitivity crosses certain critical values. We obtain two kinds of important patterns, which are induced by chemotaxis: stationary Turing pattern and irregular oscillatory pattern. We also find that different chemotactic response functions can affect system's dynamics. Based on some empirical parameter values, numerical simulations are given to illustrate the effectiveness of the theoretical predications. [ABSTRACT FROM AUTHOR]

Malignant glioma is an aggressive primary brain tumor. Due to its location, the interactions of glioma and the immune system are complex. We start this paper by proposing a simple mathematical model that describes the interaction among glioma cells, microglia and cytotoxic T lymphocytes (CTLs). The existence and stability conditions of the equilibrium points are analyzed. Numerical results showed that neither microglia nor CTLs has the ability to eradicate the tumor. As a result, we extend the model by including the chemotherapeutic agent. The model has six equilibrium points, and one of these points represents a cured state. Through local stability, we found a range of values for the infusion rate that guarantees the elimination of glioma, as well as preventing the glioma from reoccurring. [ABSTRACT FROM AUTHOR]

In this paper, we offer a new modelling approach for hepatitis C virus (HCV) infection models with cytotoxic T lymphocytes (CTL) immune responses. The standard neural network models with reaction-diffusion terms are generalized to the discontinuous case considering impulsive controllers. Also, the conformable approach is proposed as a more adjustable modelling apparatus which overcomes existing difficulties in the application of the fractional-order modelling technique. In addition, the existence of integral manifolds for the proposed model is investigated and efficient criteria are established. Since stability and control of a neural network model are essential for its proper application, stability results for the constructed integral manifold are presented. These results extend and generalize the stability results for steady states of proposed HCV models with CTL immune responses and contribute to the development of new innovative modelling approaches in biology. The qualitative analysis is performed via the conformable Lyapunov function method. The established results are demonstrated through an example. [ABSTRACT FROM AUTHOR]

Objective(s): In this study, the adjuvant activity of aqueous and alcoholic extracts of propolis was examined on the inactivated herpes simplex virus-1 (HSV-1). Materials and Methods: BALB/C mice were administered with inactivated (HSV-1; the KOS strain) plus alcoholic and aqueous extracts, followed by assessment of the cellular and humoral immune responses. Results: Alcoholic and aqueous extracts, as an adjuvant, revealed a significant increase in lymphocyte proliferation and cytotoxic T lymphocyte (CTL) responses versus the HSV-1 group. In addition, HSV-1 plus alcoholic extract showed a remarkable increase in IFN-γ cytokine and IFN-γ/IL-4 ratio. On the other hand, both alcoholic and aqueous extracts in the HSV-1 vaccine suppressed the IL-4 cytokine response as compared with the HSV-1 vaccine. In addition, HSV-1 plus alcoholic extract showed a significant increment in IgG1, IgG2a, and IgG2b isotypes as compared with the HSV-1 vaccine. Conclusion: Propolis extracts seem to modulate the immune response against inactivated HSV-1 model and can be used as a suitable vaccine adjuvant or a component of a complex adjuvant against infectious diseases. [ABSTRACT FROM AUTHOR]

In this paper, we incorporate immune systems containing Cytotoxic T lymphocyte and humoral immunity into a general human immunodeficiency viruses infection model, which also considers logistic growth for target cells and both modes of spread, cell-to-cell and cell-free represents, by linear functions. We derive five threshold parameters which are used to study the existence of equilibria. By considering the characteristic equations, the local stability of disease-free and immune-free equilibria is investigated. Lyapunov functions and LaSalle's invariance are constructed to prove the global stability of all steady states. Global dynamics of the human immunodeficiency viruses model can be accurately expressed by threshold parameters; also the existence of Hopf bifurcation is discussed and the results are expressed in the form of a proposition. Furthermore, numerical simulations confirm the corresponding theoretical results. [ABSTRACT FROM AUTHOR]

Vitiligo is caused by an autoimmune reaction against melanocytes leading to melanocyte loss. The cause of vitiligo is an interaction between genetic susceptibility and environmental factors. Both the adaptive immune system—through cytotoxic CD8+ T cells and melanocyte specific antibodies—and the innate immune system are involved in these immune processes in vitiligo. While recent data stressed the importance of innate immunity in vitiligo, the question remains why vitiligo patients' immune response becomes overly activated. Could a long‐term increase in innate memory function, described as trained immunity after vaccination and in other inflammatory diseases, play a role as an enhancer and continuous trigger in the pathogenesis of vitiligo? After exposure to certain stimuli, innate immune system is able to show an enhanced immunological response to a secondary trigger, indicating a memory function of the innate immune system, a concept termed trained immunity. Trained immunity is regulated by epigenetic reprogramming, including histone chemical modifications and changes in chromatin accessibility that cause sustained changes in the transcription of specific genes. In responses to an infection, trained immunity is beneficial. However, there are indications of a pathogenic role of trained immunity in inflammatory and autoimmune diseases, with monocytes presenting features of a trained phenotype, resulting in increased cytokine production, altered cell metabolism through mTOR signaling, and epigenetic modifications. This hypothesis paper focusses on vitiligo studies that have shown these indications, suggesting the involvement of trained immunity in vitiligo. Future studies focusing on metabolic and epigenetic changes in innate immune cell populations in vitiligo could help in elucidating the potential role of trained immunity in vitiligo pathogenesis. [ABSTRACT FROM AUTHOR]

According to the latest evidence, the microbial metabolite Urolithin A (UA), known for its role in promoting cellular health, modulates CD8+ T cell‐mediated antitumor activity. However, the direct target protein of UA and its underlying mechanism remains unclear. Here, this research identifies ERK1/2 as the specific target crucial for UA‐mediated CD8+ T cell activation. Even at low doses, UA markedly enhances the persistence and effector functions of primary CD8+ cytotoxic T lymphocytes (CTLs) and human chimeric antigen receptor (CAR) T cells both in vitro and in vivo. Mechanistically, UA interacts directly with ERK1/2 kinases, enhancing their activation and subsequently facilitating T cell activation by engaging ULK1. The UA‐ERK1/2‐ULK1 axis promotes autophagic flux in CD8+ CTLs, enhancing cellular metabolism and maintaining reactive oxygen species (ROS) levels, as evidenced by increased oxygen consumption and extracellular acidification rates. UA‐treated CD8+ CTLs also display elevated ATP levels and enhanced spare respiratory capacity. Overall, UA activates ERK1/2, inducing autophagy and metabolic adaptation, showcasing its potential in tumor immunotherapy and interventions for diseases involving ERKs. [ABSTRACT FROM AUTHOR]

Innovations in cancer immunotherapy have resulted in the development of several novel immunotherapeutic strategies that can disrupt immunosuppression. One key advancement lies in immune checkpoint inhibitors (ICIs), which have shown significant clinical efficacy and increased survival rates in patients with various therapy-resistant cancers. This immune intervention consists of monoclonal antibodies directed against inhibitory receptors (e.g., PD-1) on cytotoxic CD8 T cells or against corresponding ligands (e.g., PD-L1/PD-L2) overexpressed on cancer cells and other cells in the tumor microenvironment (TME). However, not all cancer cells respond—there are still poor clinical responses, immune-related adverse effects, adaptive resistance, and vulnerability to ICIs in a subset of patients with cancer. This challenge showcases the heterogeneity of cancer, emphasizing the existence of additional immunoregulatory mechanisms in many patients. Therefore, it is essential to investigate PD-L1's interaction with other oncogenic genes and pathways to further advance targeted therapies and address resistance mechanisms. Accordingly, our aim was to investigate the mechanisms governing PD-L1 expression in tumor cells, given its correlation with immune evasion, to uncover novel mechanisms for decreasing PD-L1 expression and restoring anti-tumor immune responses. Numerous studies have demonstrated that the upregulation of Raf Kinase Inhibitor Protein (RKIP) in many cancers contributes to the suppression of key hyperactive pathways observed in malignant cells, alongside its broadening involvement in immune responses and the modulation of the TME. We, therefore, hypothesized that the role of PD-L1 in cancer immune surveillance may be inversely correlated with the low expression level of the tumor suppressor Raf Kinase Inhibitor Protein (RKIP) expression in cancer cells. This hypothesis was investigated and we found several signaling cross-talk pathways between the regulations of both RKIP and PD-L1 expressions. These pathways and regulatory factors include the MAPK and JAK/STAT pathways, GSK3β, cytokines IFN-γ and IL-1β, Sox2, and transcription factors YY1 and NFκB. The pathways that upregulated PD-L1 were inhibitory for RKIP expression and vice versa. Bioinformatic analyses in various human cancers demonstrated the inverse relationship between PD-L1 and RKIP expressions and their prognostic roles. Therefore, we suspect that the direct upregulation of RKIP and/or the use of targeted RKIP inducers in combination with ICIs could result in a more targeted anti-tumor immune response—addressing the therapeutic challenges related to PD-1/PD-L1 monotherapy alone. [ABSTRACT FROM AUTHOR]

Yellow fever outbreaks are prevalent, particularly in endemic regions. Given the lack of an established treatment for this disease, significant attention has been directed toward managing this arbovirus. In response, we developed a multiepitope vaccine designed to elicit an immune response, utilizing advanced immunoinformatic and molecular modeling techniques. To achieve this, we predicted B- and T-cell epitopes using the sequences from all structural (E, prM, and C) and nonstructural proteins of 196 YFV strains. Through comprehensive analysis, we identified 10 cytotoxic T-lymphocyte (CTL) and 5T-helper (Th) epitopes that exhibited overlap with B-lymphocyte epitopes. These epitopes were further evaluated for their affinity to a wide range of human leukocyte antigen system alleles and were rigorously tested for antigenicity, immunogenicity, allergenicity, toxicity, and conservation. These epitopes were linked to an adjuvant (β -defensin) and to each other using ligands, resulting in a vaccine sequence with appropriate physicochemical properties. The 3D structure of this sequence was created, improved, and quality checked; then it was anchored to the Toll-like receptor. Molecular Dynamics and Quantum Mechanics/Molecular Mechanics simulations were employed to enhance the accuracy of docking calculations, with the QM portion of the simulations carried out utilizing the density functional theory formalism. Moreover, the inoculation model was able to provide an optimal codon sequence that was inserted into the pET-28a(+) vector for in silico cloning and could even stimulate highly relevant humoral and cellular immunological responses. Overall, these results suggest that the designed multi-epitope vaccine can serve as prophylaxis against the yellow fever virus. [ABSTRACT FROM AUTHOR]

Understanding at the molecular level of the cell biology of tumors has led to significant treatment advances in the past. Despite such advances however, development of therapy resistance and tumor recurrence are still unresolved major challenges. This therefore underscores the need to identify novel tumor targets and develop corresponding therapies to supplement existing biologic and cytotoxic approaches so that a deeper and more sustained treatment responses could be achieved. The complement system is emerging as a potential novel target for cancer therapy. Data accumulated to date show that complement proteins, and in particular C1q and its receptors cC1qR/CR and gC1qR/p33/HABP1, are overexpressed in most cancer cells and together are involved not only in shaping the inflammatory tumor microenvironment, but also in the regulation of angiogenesis, metastasis, and cell proliferation. In addition to the soluble form of C1q that is found in plasma, the C1q molecule is also found anchored on the cell membrane of monocytes, macrophages, dendritic cells, and cancer cells, via a 22aa long leader peptide found only in the A-chain. This orientation leaves its 6 globular heads exposed outwardly and thus available for high affinity binding to a wide range of molecular ligands that enhance tumor cell survival, migration, and proliferation. Similarly, the gC1qR molecule is not only overexpressed in most cancer types but is also released into the microenvironment where it has been shown to be associated with cancer cell proliferation and metastasis by activation of the complement and kinin systems. Co-culture of either T cells or cancer cells with purified C1q or anti-gC1qR has been shown to induce an anti-proliferative response. It is therefore postulated that in the tumor microenvironment, the interaction between C1q expressing cancer cells and gC1qR bearing cytotoxic T cells results in T cell suppression in a manner akin to the PD-L1 and PD-1 interaction. [ABSTRACT FROM AUTHOR]

The existence of HIV post-treatment controllers (PTCs) offers hope for an HIV functional cure, and understanding the critical mechanisms determining PTC represents a key step toward this goal. Here, we have studied these mechanisms by analyzing an established mathematical model for HIV viral dynamics. In mathematical models, critical mechanisms are represented by parameters that affect the tipping points to induce qualitatively different dynamics, and in cases with multiple stability, the initial conditions of the system also play a role in determining the fate of the solution. As such, for the tipping points in parameter space, we developed and implemented a sensitivity analysis of the threshold conditions of the associated bifurcations to identify the critical mechanisms for this model. Our results suggest that the infected cell death rate and the saturation parameter for cytotoxic T lymphocyte proliferation significantly affect post-treatment control. For the case with multiple stability, in state space of initial conditions, we first investigated the saddletype equilibrium point to identify its stable manifold, which delimits trapping regions associated to the high and low viral set points. The identified stable manifold serves as a guide for the loads of immune cells and HIV virus at the time of therapy termination to achieve post-treatment control. [ABSTRACT FROM AUTHOR]

Personalized cancer vaccines based on resected tumors from patients is promising to address tumor heterogeneity to inhibit tumor recurrence or metastasis. However, it remains challenge to elicit immune activation due to the weak immunogenicity of autologous tumor antigens. Here, a hybrid membrane cancer vaccine is successfully constructed by membrane fusion to enhance adaptive immune response and amplify personalized immunotherapy, which formed a codelivery system for autologous tumor antigens and immune adjuvants. Briefly, the functional hybrid vesicles (HM‐NPs) are formed by hybridizing ginseng‐derived extracellular vesicles‐like particles (G‐EVLPs) with the membrane originated from the resected autologous tumors. The introduction of G‐EVLPs can enhance the phagocytosis of autologous tumor antigens by dendritic cells (DCs) and facilitate DCs maturation through TLR4, ultimately activating tumor‐specific cytotoxic T lymphocytes (CTLs). HM‐NPs can indeed strengthen specific immune responses to suppress tumors recurrence and metastasis including subcutaneous tumors and orthotopic tumors. Furthermore, a long‐term immune protection can be obtained after vaccinating with HM‐NPs, and prolonging the survival of animals. Overall, this personalized hybrid autologous tumor vaccine based on G‐EVLPs provides the possibility of mitigating tumor recurrence and metastasis after surgery while maintaining good biocompatibility. [ABSTRACT FROM AUTHOR]