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In this Q&A, Cell Press Community Review Scientific Editor Leia Judge talks to Dr. Clint Allen and Dr. Sandro Santagata about their new papers "Phenotypic plasticity and reduced tissue retention of exhausted tumor-infiltrating T cells following neoadjuvant immunotherapy in head and neck cancer" and "Lymphocyte networks are dynamic cellular communities in the immunoregulatory landscape of lung adenocarcinoma" and their experiences with publishing through Cell Press Community Review. [ABSTRACT FROM AUTHOR]

Abstract This paper is mainly concerned with an investigation of antigen-driven T-cell infection process through a mathematical model. Several mathematical models have been introduced in the literature in order to gain insights into the dynamics of the disease progression, however, the results considering the effect of multiple factors which include antigen-driven CD4 T-cell progress, latent infection stage, activation of CTLs response, role of antiretroviral therapies (ARTs) and possibilities of multiple time-delays during the infection process are not involved. Hence, the paper introduces a six-dimensional virus infection model by involving the above factors. Particularly, (i) the effect of activation of antigen-specific T-cells; (ii) the effect of the maturation of infected cells; (iii) effect of multiple time delays, that is, during the interaction between susceptible and infectious and during the activation of immune responses; which play a significant role in preventing and modulating the Human Immunodeficiency Virus (HIV). The main aim of the paper to analyze the local and global stability of the class of mathematical models regarding the effect of time delays which provides a better pathway to the infection progress. Finally, the overall contribution of the present work is listed as follows: (1) by constructing the suitable Lyapunov functional, the global stability of the intracellular delayed model is derived; (2) detailed Hopf-bifurcation analysis is discussed with respect to immune response delay. The numerical simulation is performed to validate the effectiveness and applicability of the theoretical predictions. [ABSTRACT FROM AUTHOR]

α-Galactosyl ceramide (GalCer) as a glycolipid has been long used as a standard reference for positive control in natural killer T cell studies. The (1,2)-disaccharide analogue of GalCer attracts a special attention in the study of lysosomal glycolipid processing. This paper describes the synthesis and self-assembly behaviors of GalCer 1,2-polysaccharide analogue (PolyGalCer), having considered the 1,2-disaccharide analogue as a structural motif. The synthesis of PolyGalCer is performed via one-pot glycosidation technique of 1,2-linked oligogalactan exploiting chain polymerization of galactose-based cyclic sulfite as a monomer initiated with ceramide-based alcoholic aglycon. Through the concentration dependence of PolyGalCer solutions in water or in MeOH on the turbidity, it is found that PolyGalCer forms associates in both media. From the intersection points, the critical aggregation concentration (CAC) values of PolyGalCer in water and MeOH were estimated. To know the self-assembly and the thermal transition behaviors, we performed dynamic light scattering (DLS) analysis of the associates comprising PolyGalCer in water. The transmission electron microscopy observations of the aqueous sample solution indicate that the solution of PolyGalCer includes large spherical associates. The results clarify that the 1,2-galactan moiety of PolyGalCer skeleton contributes on the kinetic inhibition of large associate formation and the metamorphosis of associates. [Display omitted] [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) can establish infection via two distinct modes: virus-to-cell infection and cell-to-cell transmission. These infections prompt the activation of two types of adaptive immune responses: the cytotoxic T lymphocyte response and the antibody response. In this paper, we study HCV dynamics by developing a multiscale model that incorporates both modes of infection as well as the two types of immune responses. We derive both the basic reproduction number of virus and four immune reproduction numbers for the model. We identify five equilibria, the existence of which depends on the values of basic reproduction number of virus and the immune reproduction numbers. We also establish the global asymptotic stability of the equilibria by employing Lyapunov functions, which further underscores the profound impact of the aforementioned reproduction numbers on the model's overall stability. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages (TAMs), the main components of infiltrating leukocytes in tumors, often play a key role in promoting cancer development and progression. The tumor-specific microenvironment forces the phenotype of tumor-infiltrating to evolve in a direction favorable to tumor development, that is, the generation of M2-like TAMs. Consequently, the dual intervention of cancer cells and tumor microenvironment has become a research hotspot in the field of tumor immunotherapy. In this contribution, we developed pH-sensitive mesoporous calcium silicate nanocomposites (MCNs) encapsulated with indocyanine green (ICG) to enable the effective combination of photothermal therapy (PTT) and photodynamic therapy (PDT) triggered by the 808 nm near-infrared (NIR) light. The mannose and hyaluronic acid-grafted MCNs specifically targeted TAMs and tumor cells and promoted cell apoptosis both in vitro and in vivo. This paper revealed that irradiation of ICG loaded MCNs with NIR can produce a potent hyperthermia and induce abundant intracellular singlet oxygen generation in the target cells. These results suggest that the novel nanoplatform is believed to facilitate the delivery of chemotherapeutic agents to the tumor microenvironment (TME) to enhance the effects of tumor treatment. [Display omitted] [ABSTRACT FROM AUTHOR]

Discrete tissue niches are emerging as essential prerequisites enabling cell communication and function in both homeostasis and disease. In a recent Cell paper, Di Pilato et al. identify a unique dendritic cell-cytotoxic T cell crosstalk within the perivascular space that facilitates T cell survival and proliferation and drives anti-tumor activity. [ABSTRACT FROM AUTHOR]

Hybrid branching-time logics are a powerful extension of branching-time logics like CTL, CTL⁎ or even the modal μ -calculus through the addition of binders, jumps and variable tests. Their expressiveness is not restricted by bisimulation-invariance anymore. Hence, they do not retain the tree model property, and the finite model property is equally lost. Their satisfiability problems are typically undecidable, their model checking problems (on finite models) are decidable with complexities ranging from polynomial to non-elementary time. In this paper we study the expressive power of such hybrid branching-time logics. We extend the hierarchy of branching-time logics CTL, CTL+, CTL⁎ and the modal μ -calculus to their hybrid extensions. We show that most separation results can be transferred to the hybrid world, even though the required techniques become more involved. We also present collapse results for linear, tree-shaped and finite models. [ABSTRACT FROM AUTHOR]

Presentation of exogenous antigens loaded on major histocompatibility complex class I molecules by antigen presenting cells, termed cross-presentation, is essential for the induction of CD8+ T cells and is performed mainly by specialized dendritic cell subsets. Research into this field has described two main mechanisms of cross-presentation, the cytosolic pathway and the vacuolar pathway. As the first step in cross-presentation, surface receptors relating to cross-presentation are required in the recognition and uptake of Ags, which include C-type lectin receptors, immunoglobulin γ Fc region receptor, chemokine receptor, scavenger receptor etc. After uptake by the cells, there are also many molecules that enable Ags to participate in cross-presentation pathways. By this approach, exogenous Ags can induce CD8+ T cells into cytotoxic T lymphocytes, which is of great significance to induce antitumor and antiviral immune responses, and the molecular mechanism would facilitate the development of related adjuvants. However, the detailed mechanisms of cross-presentation still remain unknown. In this paper, some latest researches, including two major pathways, DC surface receptors and application prospects are summarized. [ABSTRACT FROM AUTHOR]

• A new method is proposed to determine drug dose for mixed therapy in cancer treatment. • Optimal drug dose for treatment of reference patient is determined via SDRE method. • The SDRE based MRAC design method is introduced for nonlinear MIMO systems. • Personalized drug delivery for an unknown patient is determined using the MRAC method. • The continuous and bang-bang drug delivery protocols are achieved and compared. The paper presents Model Reference Adaptive Control (MRAC) design strategy to determine personalized drug delivery protocol for mixed therapy with chemotherapy and immunotherapy in cancer treatment. We consider a nonlinear mathematical ODE set for cancer dynamics that includes tumor, natural killers, circulating lymphocytes and cytotoxic T-cells population together with the interaction of chemotherapy and immunotherapy. For researchers and physicians, the main challenge in mathematical models is the determination of the exact model parameters. In order to have a drug administration policy for a patient with unknown parameter set, we develop State Dependent Riccati Equations (SDRE) based MRAC design approach to determine the personalized drug delivery protocol for patients with unknown model parameters. First of all, we determine the optimal drug delivery scenario for a reference patient with known dynamics parameters using SDRE approach. Then for any patient with unknown parameters, the personalized mixed therapy protocol is determined based on the treatment regimen of the reference patient. In the proposed methodology, unknown patients are considered as a black-box simulator in the design and the mathematical model parameters of the patient are not essential for the design of drug administration protocol. In addition, the Bang-Bang and continuous drug delivery regimens could be obtained using proper adaptation gains in the presented MRAC methodology. The simulation results demonstrate the effectiveness of the proposed MRAC approach for prescribing a treatment regimen of chemo-immunotherapy. [ABSTRACT FROM AUTHOR]

Potent adjuvants are highly demanded for most protein and peptides based vaccine candidates in clinical development. Recognition of viral single stranded (ss)RNA by innate toll-like receptors 7/8 in dendritic cells results in a cytokine environment supportive to the establishment of long lasting antibody responses and Th1 oriented T cell immunity. To fully exploit the immunestimulatory properties of ssRNA, it needs to be adequately formulated to ensure its optimal delivery to dendritic cells in the vaccine draining lymph nodes. In the present paper, we report on the design of ssRNA nanocomplexes formed by complexation of the cationic poly(carbonic acid 2-dimethylamino-ethyl ester 1-methyl-2-(2-methacryloylamino)-ethyl ester) (pHPMA-DMAE) based polymeric carrier and ssRNA. The resulting ssRNA nanocomplexes were subsequently PEGylated through copper-free click chemistry using PEG-bicyclo[6.1.0]nonyne (PEG-BCN) and cross-linked via disulfide bonds to increase their stability. The obtained near-neutral charged PEGylated ssRNA nanocomplexes (~150 nm) combined ssRNA protection with highly efficient delivery of ssRNA to DCs in the vaccine draining lymph nodes after subcutanuously administration. When co-administrated with a model antigen (soluble ovalbumin (OVA)), ssRNA nanocomplexes were far more efficient at inducing CD8 cytolytic T cells when compared to OVA co-adminstarted with naked ssRNA. Furthermore, IgG2c antibody titers, indicative of Th1 skewed T cell responses, were >10 times increased by complexing ssRNA into the PEGylated nanocomplexes. This study highlights the potential of post-functionalizing ssRNA nanocomplexes by copper-free click chemistry and these findings indcate that this potent ssRNA adjuvant may profoundly improve the efficacy of a variety of vaccines requiring Th1-type immunity. [ABSTRACT FROM AUTHOR]

[Display omitted] • Baicalein-loaded mPEG-PLGA nanoparticles with a high drug-loading rate and stability were developed, which has high biocompatibility and low toxicity. • Baicalein enables to inhibition of the TGF-β/Smad and TGF-β/MAPK signaling pathways and reduces the activation of cancer associated fibroblasts. • PMs-Ba could remodel the tumor microenvironment by baicalein-loaded mPEG-PLGA, contributing to enhancing the anti-tumor impact of adriamycin-loaded mPEG-PLGA. Cancer-associated fibroblasts constitute a significant component in the tumor microenvironment, playing a pivotal role in tumor proliferation, invasion, migration, and metastasis. Consequently, therapy combining chemotherapeutic agents with tumor microenvironment (TME) modulators appears to be a promising avenue for cancer treatment. In this paper, a tumor microenvironment-based mPEG-PLGA nanoparticle loaded with baicalein (PMs-Ba) was constructed for the purpose of improving the tumor microenvironment in cases of triple-negative breast cancer. The results demonstrate that, on the one hand, PMs-Ba was able to inhibit the transforming growth factor β(TGF-β) signaling pathway to avoid the activation of cancer-associated fibroblasts (CAFs), thereby influencing the interstitial microenvironment of the tumor. On the other hand, the agent led to an increase in the infiltration of cytotoxic T cells, activating the tumor immune microenvironment. Meanwhile, in the murine breast cancer model, an intravenous injection of PMs-Ba combined with doxorubicin nanoparticles (PMs-ADM) significantly improved the antitumor effectiveness. These results suggest that baicalein encapsulated in nanoparticles may be a promising strategy for modulating the TME and for adjuvant chemotherapy, signifying a potential TME-remodeling nanoformulation that could enhance the antitumor efficacy of nanotherapeutics. [ABSTRACT FROM AUTHOR]

• To demonstrate the Galerkin method's validity, via the accuracy of its predictions using DPDE models. • To structure a process for applying the theoretical framework to find theoretical results. • To show the impacts of diffusion and immune response delay on the model, through bifurcation diagrams. • To determine the steady-state solutions, Hopf points, and the stable and unstable zones. • To illustrate comparisons of the DDE and DPDE approaches through a selection of 2-D and 3-D solution maps. This paper studies a diffusive viral infection system with delayed immune response in the one-domain system. A system of DDE equations was explored, both analytically and numerically, using the Galerkin method. A condition that helps to find Hopf bifurcation points is determined. Full maps of the Hopf bifurcation points as well regions of stability are constructed and considered in detail. It is shown that the time delay of cytotoxic T lymphocyte (CTL) response and the diffusion parameter can significantly impact upon the stability regions. Furthermore, the influences of the other free values have been examined for their effects on stability. It is found that, as diffusion increases, the CTL response delay increases, and also as the CTL response delay is increased, the Hopf points for both generation rate and activate rate are decreased, whereas the Hopf points for the infection and death rates increased. Moreover, an increase diffusion results in an increase in the Hopf points for growth rate and activation rate, while the Hopf bifurcations are decreased for the death rate of infected cells. Bifurcation diagrams are plotted to show selected examples of limit cycle behavior (periodic oscillation), and 3-D solutions for the three concentrations in the model have been plotted to corroborate all analytical results from the theoretical section. [ABSTRACT FROM AUTHOR]

Malaria is a life-threatening disease caused by infection with Plasmodium parasites. The goal of developing an effective malaria vaccine is yet to be reached despite decades of massive research efforts. CD4+ helper T cells, CD8+ cytotoxic T cells, and γδ T cells are associated with immune responses to both liver-stage and blood-stage Plasmodium infection. The immune responses of T cell-lineages to Plasmodium infection are associated with both protection and immunopathology. Studies with mouse model of malaria contribute to our understanding of host immune response. In this paper, we focus primarily on mouse malaria model with blood-stage Plasmodium berghei infection and review our knowledge of T cell immune responses against Plasmodium infection. Moreover, we also discuss findings of experimental human studies. Uncovering the precise mechanisms of T cell-mediated immunity to Plasmodium infection can be accomplished through further investigations using mouse models of malaria with rodent Plasmodium parasites. Those findings would be invaluable to advance the efforts for development of an effective malaria vaccine. [ABSTRACT FROM AUTHOR]

The goal of this paper is to study the threshold dynamics of an HIV-1 viral infection model with cell-mediated immune responses and direct cell-to-cell transmission mechanism. The model demonstrates global threshold dynamics with respect to the reproductive numbers for viral infection ℜ 0 and for CTL immune response ℜ 1 . The proofs of main results come from suitable uses of analyzing the characteristic equation and constructing Lyapunov functionals. Specifically, if ℜ 0 < 1, the infection-free equilibrium E 0 is locally and globally asymptotically stable, and the viruses are cleared. If ℜ 1 < 1 < ℜ 0 , the CTL-inactivated equilibrium E 1 is locally and globally asymptotically stable, and the infection becomes chronic but without persistent CTLs response. If ℜ 1 > 1, the CTL-activated equilibrium E 2 is locally and globally asymptotically stable, and the infection is chronic with persistent CTLs response. Numerical simulations are performed to support our results. [ABSTRACT FROM AUTHOR]

Prostate brachytherapy (BT), with either low-dose-rate (LDR) or high-dose-rate (HDR), delivers a highly conformal and heterogeneous dose, allowing for dose escalation beyond external beam radiotherapy (EBRT). Whether this different dose deposition results in opportunistic biological changes that could be harnessed to improve outcomes is not well studied. Given the increasing interest in incorporating immunotherapy into prostate cancer treatment, we sought to investigate the impact of prostate BT on the immune system. A scoping review was performed using PubMed and Scopus for papers published between 2011-2021. Search terms used were "brachytherapy" AND "immune" AND "prostate". A total of 62 records were identified. After review, 6 studies were identified for review that included information an immune assessment on patient samples (tissue and/or blood) after prostate BT. 2 LDR studies (N=68) evaluated changes in the peripheral blood following I-125 BT monotherapy. Both studies demonstrated significant increases in peripheral CD3+ T cells and CD4+ T cells post-BT. However, increased circulating CD8+ T cells were observed in only one study. One study also demonstrated significant increases in Treg subsets up to 150 days post-treatment, which may be compensatory to increased cytotoxic T cell titers. 4 HDR studies (N=37) were identified (HDR fraction sizes 10-15 Gy), and all were done in combination with EBRT. Androgen deprivation therapy was included, for select patients, and one study included nivolumab. Three looked at changes in tissue immune infiltrates seen in post-BT biopsies and 1 looked at changes in both tissue and blood. The largest study (N=24) showed a single 10 Gy fraction of HDR converted 80% of "cold" tumors into an "intermediate" or "hot" state, based on a tumor inflammation signature, when comparing a pre-BT biopsy to a biopsy done prior to HDR fraction 2. In another study (N=6) a significant correlation between increased pathologic response (no tumor in ≥ 4/6 cores) and increased CD4+ and CD8+ T cells in prostate tissue as well as CD4+ T cells in the blood was seen (p values not reported). Tumor infiltrating lymphocyte recruitment may be context dependent given a case report demonstrated decreased T cell infiltration post BT+EBRT. Finally, in a separate study (N=6), peripheral blood analysis demonstrated increased CD8+ T cells with an activated phenotype, decreased CD4+/CD8+ T ratio, decreased CD4+ helper T cells, and increased CD4+PD1+ cells at 3 months post-treatment when compared to baseline levels EBRT. Patients with PSA<0.02 at 3 months were also more likely to have increased CD4+ PD1+ T cells. Both LDR and HDR BT can invoke an immune activating phenotype in prostate cancer; however, changes in immunosuppressive cells are also seen. Additional data is needed to understand how to better promote synergy between these changes and improving clinical outcomes. [ABSTRACT FROM AUTHOR]

• A model for HTLV-I infection that includes uninfected & infected CD4+T cells and HTLV-I-specific CD8+T cells. • To better understand the dynamics of HTLV-I infection, we incorporate a CTL immune response delay. • Applying Lyapunov functional procedures to determine global stability by the reproduction numbers R0 and R1. • The model with delay experiences a destabilization of the infected steady state leading to Hopf bifurcation and periodic solutions. • We estimate the length of delay to preserve the stability of bifurcating limit cycle using Nyquist criteria. This paper deals with a four dimensional mathematical model for Human T-cell leukemia virus type-I (HTLV-I) infection that includes delayed CD8+ cytotoxic T-cells (CTLs) immune response. The proposed system has three biologically feasible steady states, namely disease-free steady state, CTL-inactive steady state and an interior steady state. Our theoretical analysis demonstrates that local and global stability analysis are established by the two critical parameters R 0 and R 1 , basic reproduction numbers due to viral infection and due to CTLs immune response, respectively. The disease-free steady state E 0 is globally stable if R 0 ≤ 1 , and the HTLV-I infections are eliminated. The asymptotic-carrier steady state E 1 is globally stable if R 1 ≤ 1 < R 0 , which indicates HTLV-I infection is chronic without persistence of CTLs immune response. The interior steady state E 2 is globally asymptotic stable if R 1 > 1 , which implies that the HTLV-I infection is choric in persistence of CTLs immune response. Due to immune response delay, our proposed model undergoes a destabilization of the interior steady state leading to Hopf bifurcation and periodic oscillations. We estimate the length of time delay that preserve the stability of period-1 limit cycle. We also derived the direction and stability of Hopf bifurcation around the interior steady state by center manifold theory and normal form method. To determine the robustness of the model, we performed normalized forward sensitivity analysis with reference to R 0 and R 1. Our proposed model undergoes Hopf bifurcation with respect to the production rate of uninfected CD4+T cells h , removal rate of virus-specific CTLs d 4 , spontaneous infected CD4+T cell activation d 2 and transmissibility coefficient β. Implications of our numerical illustrations to the pathogenesis of HTLV-I infection and the development of HTLV-I related HAM/TSP are explored. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 infection intrigued medicine with diverse outcomes ranging from asymptomatic to severe acute respiratory syndrome (SARS) and death. After more than two years of pandemic, reports of reinfection concern researchers and physicists. Here, we will discuss potential mechanisms that can explain reinfections, including the aggravated ones. The major topics of this hypothesis paper are the disbalance between interferon and antibodies responses, HLA heterogeneity among the affected population, and increased proportion of cytotoxic CD4+ T cells polarization in relation to T follicular cells (Tfh) subtypes. These features affect antibody levels and hamper the humoral immunity necessary to prevent or minimize the viral burden in the case of reinfections. [ABSTRACT FROM AUTHOR]

Recently, hematopoietic stem cell (HSC) based therapy is being discussed as a possible treatment for HIV infection. The main advantage of this approach is that it limits the immune impairing effect of infection by introducing an independent influx of antigen-specific cytotoxic T lymphocytes (CTL). In this paper, we present a mathematical approach to predict the dynamics of HSC based therapy. We use a modification of a basic mathematical model for virus induced impairment of help to study how virus – immune system dynamics can be influenced by a single injection of CD8+ T lymphocytes derived from hematopoietic stem cells. Our mathematical and numerical results indicate that a single, large enough dose of genetically derived CTL may lead to restoration of the cellular immune response and result in long-term control of infection. [ABSTRACT FROM AUTHOR]

In this paper, we study a diffusive and delayed virus dynamics model with Beddington–DeAngelis incidence and CTL immune response. By constructing Lyapunov functionals, we show that if the basic reproductive number is less than or equal to one, then the infection-free equilibrium is globally asymptotically stable; if the immune reproductive number is less than or equal to one and the basic reproductive number is greater than one, then the immune-free equilibrium is globally asymptotically stable; if the immune reproductive number is greater than one, then the interior equilibrium is globally asymptotically stable. [ABSTRACT FROM AUTHOR]

The complex structure of the tumor microenvironment leads to the poor efficacy of tumor immunotherapy. The therapeutic adjuvant designed to enhance the effect of T cells by acting on the costimulatory molecule tumor necrosis factor superfamily member 9 (TNFSF9) has achieved good results. However, because some tumors are characterized by reduced T-cell infiltration, adjuvants acting on T cells alone may have limitations. On the other hand, the blockade of TNFSF9 reverse signalling can have an antitumor effect by reshaping the tumor microenvironment. Therefore, this paper mainly discusses the current status and potential of TNFSF9 bidirectional signalling in antitumor immunotherapy to provide new ideas for tumor immunotherapy. [ABSTRACT FROM AUTHOR]

In this paper, we consider the combined effects of cytotoxic T lymphocyte (CTL) responses on the competition dynamics of two Simian immunodeficiency virus (SIV) strains model. One of strains concerns a relatively slowly replicating and mildly cytopathic virus in the early infection (SIVMneCL8), the other is faster replicating and more cytopathic virus at later stages of the infection (SIVMne170). It is shown that the global dynamics of the ordinary differential equations can be determined by several threshold parameters, and we prove the global stability of the equilibria by rigorous mathematical analysis. To account for a series of infection mechanism leading to viral production, we incorporate time delays in the infection term. Using the methods of constructing suitable Lyapunov functionals and LaSalle’s invariance principle, we obtain the sufficient conditions for the global attractiveness of infection-free equilibrium with both virus strains going extinct, single-infection equilibrium with one of two virus strains out-competing the other one and the two strains coexisting infection equilibrium. We establish that the intracellular delays can destabilize the single-infection equilibrium leading to Hopf bifurcation and periodic oscillations. We show that introduction of immune responses is responsible for the coexistence of two virus strains and the intracellular delays may alter the two-strain competition results. Numerical simulations are presented to illustrate the theoretical conclusions. [ABSTRACT FROM AUTHOR]

Abstract: In this paper, an HIV-1 infection model with saturation incidence and time delay due to the CTL immune response is investigated. By analyzing corresponding characteristic equations, the local stability of each of feasible equilibria and the existence of Hopf bifurcation at the CTL-activated infection equilibrium are established, respectively. By means of Lyapunov functionals and LaSalle’s invariance principle, it is shown that the infection-free equilibrium is globally asymptotically stable when the basic reproduction ratio is less than unity. When the immune response reproductive ratio is less than unity and the basic reproductive ratio is greater than unity, the CTL-inactivated infection equilibrium of the system is globally asymptotically stable. [Copyright &y& Elsevier]

Abstract: RCAI-147 is one of the hydroxylated analogues of KRN7000 which is known as a ligand for the activation of CD1d mediated invariant natural killer T cells (iNKT cells) and releases both T helper 1 (Th1) cytokines such as IFN-γ and T helper 2 (Th2) cytokines such as IL-4. KRN7000 has been anticipated as an antitumor drug or an adjuvant for viral infection such as influenza, because of its strong secretion of IFN-γ. In an interesting twist, it has been obvious in our previous paper that RCAI-147 induces much more Th2 cytokines (IL-4) than Th1 cytokines (IFN-γ) from iNKT cells compared to KRN7000, and shows fairly good result in the experimental autoimmune encephalomyelitis (EAE) test. Therefore, synthesis of RCAI-172 (C6-OH epimer of RCAI-147) was attempted to examine the biological activity. As a result, RCAI-172 was synthesized and its biological activity biased to Th2 response largely compared to that of KRN7000. However, this level decreased to approximately 61% compared to that of RCAI-147. And the clinical score of RCAI-172 for EAE suppression was disappointing. There exist seven chiral centers in the aglycon part of RCAI-172, and even though the change of configuration is just one position (C6-OH), the effect on both Th1/Th2 response and EAE test is fairly large. [Copyright &y& Elsevier]

• Major immune effector cells like CD8+ T lymphocytes and natural killer cells are able to kill or inhibit Hepatocellular carcinoma (HCC) cells and their cytotoxic ability can be enhanced or down-regulated by certain cytokines or drugs. • HCC cells can impair the function of major immune effector cells through a variety of mechanisms. • Organoids or direct contact cell co-culture especially with primary HCC cells and tumor infiltrating lymphocytes provide better understanding of cell–cell interactions between major immune effector cells and HCC cells. • Immunotherapy like checkpoint inhibitors and adoptive cell transfer showed notable effectiveness and safety in preventing HCC recurrence as adjuvant therapy. Hepatocellular carcinoma (HCC) is the most common liver neoplasm with high morbidity and mortality. Tumor immunotherapy might be promising adjuvant therapy for HCC after surgery. To better develop HCC immunotherapy, comprehensive understanding of cell–cell interactions between immune effector cells and HCC cells remains crucial. To review the existing studies to summarize the cell–cell interactions between major immune effector cells and HCC cells providing new data for HCC immunotherapy. A systematic review was conducted by searching PubMed database covering all papers published in recent five years up to January 2020. The guidelines of the preferred reporting items for systematic reviews were firmly followed. There are 9 studies researching the interactions between CD8+ T lymphocytes and HCC cells and 22 studies researching that between natural killer (NK) cells and HCC cells. Among the 9 studies, 6 studies reported that CD8+ T lymphocytes showed cytotoxicity towards HCC cells while 3 studies found CD8+ T lymphocytes were impaired by HCC cells. Among the 22 studies, 20 studies presented that NK cells could inhibit HCC cells. Two studies were found to report NK cell dysfunction in HCC. Based on the systematic analysis, we concluded that CD8+ T lymphocytes and NK cells can inhibit HCC cells. While in turn, HCC cells can also result in the dysfunction of those effector cells through various mechanisms. Organoids and direct contact cell co-culture with primary HCC cells and TILs should be the most innovative way to investigate the interactions and develop novel immunotherapy. [ABSTRACT FROM AUTHOR]

Abstract: Interleukin 10 is an anti-inflammatory cytokine which limits immune responses to both self and foreign antigens. Blocking IL10 at the time of immunization increases cytotoxic T cell responses in antigen experienced host, a situation similar to therapeutic vaccination for cancer and chronic viral infection, where patients usually develop ineffective immune responses to tumour or viral antigens before immunotherapy starts. Graphene oxide (GO) is a nano material often used for drug delivery and tissue engineering. In the current paper, we demonstrated that GO is able to absorb anti-IL10 receptor antibodies. The anti-IL10R antibodies absorbed in GO are slowly released and the release of absorbed antibodies is pH dependent. GO absorbed anti-IL10R antibodies are bioactive both in vitro and in vivo. GO absorbed anti-IL10R antibodies are more efficient than free anti-IL10R antibodies at eliciting LPS stimulated CD8 T cell responses. Our results suggest that GO is able to absorb anti-IL10R antibodies and absorbed anti-IL10R antibody may be useful as an adjuvant for vaccination and ideal for delivering to tumour site, and breaking of suppressive tumour environment. [Copyright &y& Elsevier]

Oral Lichen Planus (OLP) is a chronic inflammatory disorder whose exact etiology remains unknown. Inflammatory mediators, cytotoxic CD8+ T cells and mast cells have been hypothesized to mediate the pathogenesis of OLP. COVID-19 pandemic caused by SARS-CoV-2 is marked by cytokine storms in the affected patients. Altered T-cell responses marked by exhaustion of T-cell count with hyperaggressive remaining T-cells and presence of cross-reactive antibodies render infected humans as fertile grounds for development of multisystem disorders. In addition, Vitamin D deficiency in COVID-19 patients can further modify the T cell mediated immunity. Increased circulating cytokines and hyperactive CD8+ T cells can alter the oral immune barriers rendering them susceptible to oral disorders. Due to the widespread immune dysregulation, it is possible that patients of COVID-19 may develop OLP in the aftermath or during recovery. The paper explores the pathogenic mechanism behind development OLP as post-COVID condition on account of their target receptor, T-cell responses, cytokine profile, mucosal immune barriers and nutrition deficiency. [ABSTRACT FROM AUTHOR]

• A new HIV/HTLV-I co-infection model with latency and Cytotoxic T lymphocytes (CTLs) immune response is developed and rigorously analyzed. • Both silent and active infected cells have been considered. • Well-possedness of the model and existence of equilibria are established. • Global stability of the equilibria are established by means of Lyapunov functions. • We have presented numerical simulations to illustrate the effectiveness of our main results. Human immunodeficiency virus (HIV) and human T-lymphotropic virus type I (HTLV-I) are two retroviruses that attack the immune cells and impair their functions. Both HIV and HTLV-I can be transmitted between individuals through direct contact with certain body fluids from infected individuals. Therefore, a person can be co-infected with both viruses. HIV causes acquired immunodeficiency syndrome, while HTLV-I is the causative agent for adult T-cell leukemia and HTLV-I-associated myelopathy/tropical spastic paraparesis. Several mathematical models have been developed in the literature to describe the within-host dynamics of HIV and HTLV-I mono-infections. However, modeling a within-host dynamics of HIV/HTLV-I co-infection has not been involved. In the present paper, we are concerned to formulate and analyze a new HIV/HTLV co-infection model under the effect of Cytotoxic T lymphocytes (CTLs) immune response. The model describes the interaction between susceptible CD4+T cells, silent HIV-infected cells, active HIV-infected cells, silent HTLV-infected cells, Tax-expressing HTLV-infected cells, free HIV particles, HIV-specific CTLs and HTLV-specific CTLs. The HIV can spread by two routes of transmission, virus-to-cell and cell-to-cell. On the other side, HTLV-I has two modes of transmission, (i) horizontal transmission via direct cell-to-cell contact, and (ii) vertical transmission through mitotic division of Tax-expressing HTLV-infected cells. The well-posedness of the model is established by showing that the solutions of the model are nonnegative and bounded. We define a set of threshold parameters which govern the existence and stability of all equilibria of the model. We explore the global asymptotic stability of all equilibria by utilizing Lyapunov function and LaSalle's invariance principle. We have presented numerical simulations to justify the applicability and effectiveness of the theoretical results. In addition, we evaluate the effect of HTLV-I infection on the HIV dynamics and vice versa. [ABSTRACT FROM AUTHOR]

Traditionally, Ehrlich's tumor is used in experimental oncology to investigate the therapeutic capacity of different synthetic chemotherapeutic agents or to evaluate the antitumoral activity of different substances of natural origin. However, the understanding of immune mechanisms during Ehrlich carcinogenesis is still limited. In this review, we seek to describe the immune response during Ehrlich's tumor growth, and natural response without the influence of pharmacological administration, immunotherapies or concomitant challenges. The study followed the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). A systematic review was carried out that included experimental trials with mice challenged with Ehrlich's tumor. The research was carried out in three databases including MEDLINE/PubMed, Scopus, Latin American and Caribbean Literature in Health Sciences (LILACS). The searches resulted in 913 papers being found, of which 55 articles were considered eligible, and of these 55, 29 were selected for analysis. Findings indicate that there is an increase in the expression of M2 and T Helper (TH2) macrophages and of the cytokines IL-17, IL-1B, IL-6 and PGE in the ascitic form of Ehrlich. These phenotypic expressions are also found in ascitic neoplasms in humans. Ehrlich's solid tumor was characterized by increased expression of CD4, CD8, neutrophils and TNF-a, Foxp3 + and Qa-2 +, and these characteristics are analogous to human breasts cancers. It is our understanding that further studies are needed to assess the immune mechanisms in Ehrlich's tumor, since these findings can be used to improve cancer treatments that are analogous to Ehrlich's tumor. Unlabelled Image [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME) provides a guarantee for the survival and development of solid tumors. In recent years, treatment strategies for TME have set off a great upsurge in the field of cancer research. Tumor angiogenesis and tumor immune microenvironment are two important research branches of TME, and antiangiogenic therapy and immunotherapy have gradually become one important focus of cancer treatment research. More interestingly, increasing number of studies have indicated that there are complex regulatory interactions between the two treatment strategies, with multiple regulatory mechanisms involved. Based on these findings, clinical studies on the combination of immunotherapy and antiangiogenic therapy have also been carried out gradually. This combination strategy has shown good results in many types of tumors, but it also faces many challenges. The paper analysed the potential mechanism of the immunotherapy and antiangiogenic therapy combination, discussed the latest significant clinical trial progress and the existing challenges and problems, aiming to offer some available insights on the effective clinical application of this combination pattern. Unlabelled Image [ABSTRACT FROM AUTHOR]

Patients who fail to adequately reconstitute the donor-derived immune system after allogeneic hematopoietic stem cell transplantation (HSCT) are at increased risk for infections and leukemia relapse. In the past, pan T-cell depleted haploidentical grafts were associated with delayed immune reconstitution (IR). Recently, the majority of patients receiving αβ T-cell/B-cell depleted haploidentical HSCT (αβhaplo-HSCT) reach a threshold of 200 CD3+ T cells/mcl by 100 days after HSCT (Bertaina A et al. Blood 2014 Jul 31;124(5):822-6). However, a proportion of patients experience a slower IR with consequent higher morbidity and mortality. Early prediction of delayed IR may permit prompt clinical intervention such as infusion of donor lymphocytes or of virus-specific cytotoxic T cells. Flow cytometry, the most widely applied approach for IR analysis, suffers from intrinsic limitations, such as high lymphocyte number requirement, degradation of samples, and insufficient standardization due to technical and operator variability. To overcome these limitations, we used a DNA methylation-based quantitative PCR that detects the epigenetic signature of different peripheral blood immune cell subsets (epigenetic quantification). This technique provides relative and absolute immune cell counts applicable to fresh, frozen, or paper-spotted dried blood. Epigenetic measurements are based on a per cell DNA copy number and provide a clear positive or negative signal rather than arbitrarily defined thresholds for "positivity" as in flow cytometry. We hypothesize that epigenetic quantification at day 15 after αβhaplo-HSCT could predict flow-based IR at day 100. Patients were consented at Lucile Packard Children's Hospital (Stanford, CA). Blood was collected between days 10-17 for epigenetic quantification and days 82-124 for flow cytometry. Bisulfite treated DNA underwent qPCR quantification of cell type-specific DNA regions of de-methylation (Baron U et al. Sci Transl Med 2018 Aug 1;10(452):eaan3508). Flow cytometry was performed using directly conjugated antibodies. Absolute cell counts were determined, plotted, and then analyzed using a linear regression model. In the first 5 αβhaplo-HSCT patients evaluated, we found a direct correlation between the epigenetic quantification at day 15 and flow cytometry at day 100 for CD4+ T cells (P=0.01), while the early epigenetic quantification of CD3+ and CD8+ T cells was not informative (Fig. 1). Preliminary data suggest that the use of epigenetic quantification early after αβhaplo-HSCT can predict the IR of CD4+ T cells at day 100 in αβhaplo-HSCT recipients. Ongoing analysis on a larger cohort of both αβhaplo-HSCT and unmanipulated HSCT recipients, will confirm if epigenetic quantification results obtained early post-HSCT can be used as a clinical biomarker of delayed IR and guide physicians in the use of post-HSCT adoptive immunotherapy. [ABSTRACT FROM AUTHOR]