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A mathematical model for the quantitative analysis of the interaction between cancer cells and cell-mediated immune system with two discrete-time delays, considering the role of antibodies, is studied in this paper. The model is analyzed both analytically and numerically to understand the dynamics of interaction delay and proliferation enhancement effect delay in the eradication of cancer. Hopf bifurcation occurs when one-time delay crosses the critical value in the absence of the other. It is also observed that as we increase any of the delays, it will increase the cancer burden. The analysis shows that a cancer-free state cannot be obtained solely by the killing rate of cytotoxic T-lymphocytes, but humoral response in combination with cell-mediated immune responses plays an important role to eradicate cancer. [ABSTRACT FROM AUTHOR]

HIV and HTLV-I are two retroviruses that infect the CD 4 + T cells. 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. It is not surprising that a mono-infected patient with one of these viruses can be exposure to co-infect with the other virus since they share the same way of transmissions between individuals, through direct contact with certain contaminated body fluids. Mathematical modeling and analysis of HIV and HTLV-I mono-infections have received considerable attention during the last decades. However, the dynamics of HIV/HTLV-I co-infection has not been formulated. In the present paper, we formulate a new HIV/HTLV-I co-infection model with cytotoxic T lymphocytes (CTLs) immune response. The model describes the interaction between susceptible CD 4 + T cells, HIV-infected cells, Tax-expressing HTLV-infected cells, free HIV particles, HIV-specific CTLs and HTLV-specific CTLs. The HIV can spread by virus-to-cell and cell-to-cell transmissions, while the HTLV-I can only spread via cell-to-cell transmission. The well-posedness of the model is established by showing that the solutions of the model are nonnegative and bounded. We derive the threshold parameters which govern the existence and stability of all equilibria of the model. We prove the global asymptotic stability of all equilibria by utilizing Lyapunov function and applying Lyapunov–LaSalle asymptotic stability theorem. We present numerical simulations to illustrate the effectiveness of our main results. In addition, we discuss the effect of HTLV-I infection on the HIV-infected patients and vice versa. [ABSTRACT FROM AUTHOR]

Lytic cell death triggers an antitumour immune response. However, cancer cells evade lytic cell death by several mechanisms. Moreover, a prolonged and uncontrolled immune response conversely leads to T-cell exhaustion. Therefore, an oncolytic system capable of eliciting an immune response by killing cancer cells in a controlled manner is needed. Here, we establish a micro-scale cytotoxic T-cell-inspired oncolytic system (TIOs) to precisely lyse cancer cells by NIR-light-controlled lipid peroxidation. Our TIOs present antigen-based cell recognition, tumour-targeting and catalytic cell-lysis ability; thus, the TIOs induce oncolysis in vivo. We apply TIOs to preclinical cancer models, showing anti-tumor activity with negligible side-effects. Tumour regression is correlated with a T-cell based anti-tumour immune response and TIOs also improve responses to anti-PD-1 therapy or STING activation. Our study provides insights to design oncolytic systems for antitumour immunity. Moreover, activation of STING can reverse T-cell exhaustion in oncolysis. Different types of lytic cell death can trigger an anti-tumor immune response. Here the authors report the design of a near infrared light controllable micron-scale oncolytic system, triggering lipid peroxidation and lytic cell death in tumors as well anti-tumor immunity in preclinical cancer models. [ABSTRACT FROM AUTHOR]

In this work, we analyse the dynamics of a five-dimensional hepatitis C virus infection mathematical model including the spatial mobility of hepatitis C virus particles, the transmission of hepatitis C virus infection by mitosis process of infected hepatocytes with logistic growth, time delays, antibody response and cytotoxic T lymphocyte (CTL) immune response with general incidence functions for both modes of infection transmission, namely virus-to-cell as well as cell-to-cell. Firstly, we prove rigorously the existence, the uniqueness, the positivity and the boundedness of the solution of the initial value and boundary problem associated with the new constructed model. Secondly, we found that the basic reproductive number is the sum of the basic reproduction number determined by cell-free virus infection, determined by cell-to-cell infection and determined by proliferation of infected cells. It is proved the existence of five spatially homogeneous equilibria known as infection-free, immune-free, antibody response, CTL response and antibody and CTL responses. By using the linearization methods, the local stability of the latter is established under some rigorous conditions. Finally, we proved the existence of periodic solutions by highlighting the occurrence of a Hopf bifurcation for a certain threshold value of one delay. [ABSTRACT FROM AUTHOR]

Pronounced immune escape by the SARS-CoV-2 Omicron variant has resulted in many individuals possessing hybrid immunity, generated through a combination of vaccination and infection. Concerns have been raised that omicron breakthrough infections in triple-vaccinated individuals result in poor induction of omicron-specific immunity, and that prior SARS-CoV-2 infection is associated with immune dampening. Taking a broad and comprehensive approach, we characterize mucosal and blood immunity to spike and non-spike antigens following BA.1/BA.2 infections in triple mRNA-vaccinated individuals, with and without prior SARS-CoV-2 infection. We find that most individuals increase BA.1/BA.2/BA.5-specific neutralizing antibodies following infection, but confirm that the magnitude of increase and post-omicron titres are higher in the infection-naive. In contrast, significant increases in nasal responses, including neutralizing activity against BA.5 spike, are seen regardless of infection history. Spike-specific T cells increase only in infection-naive vaccinees; however, post-omicron T cell responses are significantly higher in the previously-infected, who display a maximally induced response with a highly cytotoxic CD8+ phenotype following their 3rd mRNA vaccine dose. Responses to non-spike antigens increase significantly regardless of prior infection status. These findings suggest that hybrid immunity induced by omicron breakthrough infections is characterized by significant immune enhancement that can help protect against future omicron variants. The authors characterize immune response in Omicron-infected vaccinated individuals and observe an immune enhancement. While increases in neutralizing antibodies and spike T cells are stronger in previously naïve individuals, mucosal antibodies and non-spike responses increase regardless of infection history. [ABSTRACT FROM AUTHOR]

Lack of sufficient cytotoxic T lymphocytes (CD8+ T cells) infiltration and dysfunctional state of CD8+ T cells are considered enormous obstacles to antitumor immunity. Herein, we construct a synergistic nanoplatform to promote CD8+ T cell infiltration in tumors while restoring T cell function by regulating methionine metabolism and activating the STING innate immune pathway. The CRISPR/Cas9 system down-regulates the methionine transporter SLC43A2 and restricts the methionine uptake by tumor cells, thereby relieving the methionine competition pressure of T cells; simultaneously, the released nutrition metal ions activate the cGAS/STING pathway. In this work, the described nanoplatform can enhance the effect of immunotherapy in preclinical cancer models in female mice, enhancing STING pathway mediated immunity and facilitating the development of amino acid metabolic intervention-based cancer therapy. Metabolic pressure, in particular the lack of methionine availability, on tumor-infiltrating CD8 + T cells is associated with T cell dysfunction. Since tumor cells rely on SLC43A2 for methionine uptake, here the authors design a nanoplatform for CRISPR/Cas9 mediated silencing of SLC43A2 and STING activation, restoring anti-tumor T cell immune responses. [ABSTRACT FROM AUTHOR]

IFNγ is an immune mediator with concomitant pro- and anti-tumor functions. Here, we provide evidence that IFNγ directly acts on intra-tumoral CD8 T cells to restrict anti-tumor responses. We report that expression of the IFNγ receptor β chain (IFNγR2) in CD8 T cells negatively correlates with clinical responsiveness to checkpoint blockade in metastatic melanoma patients, suggesting that the loss of sensitivity to IFNγ contributes to successful antitumor immunity. Indeed, specific deletion of IFNγR in CD8 T cells promotes tumor control in a mouse model of melanoma. Chronic IFNγ inhibits the maintenance, clonal diversity and proliferation of stem-like T cells. This leads to decreased generation of T cells with intermediate expression of exhaustion markers, previously associated with beneficial anti-tumor responses. This study provides evidence of a negative feedback loop whereby IFNγ depletes stem-like T cells to restrict anti-tumor immunity. Targeting this pathway might represent an alternative strategy to enhance T cell-based therapies. IFN-γ is associated with the efficacy of anti-tumour immune responses, and both pro- and anti-tumour functions have been ascribed to this cytokine. Here, the authors demonstrate that IFN-γ signalling inhibits the maintenance of stem-like T cells, thereby impairing anti-tumour immune responses. [ABSTRACT FROM AUTHOR]

In situ vaccination is a promising strategy to convert the immunosuppressive tumor microenvironment into an immunostimulatory one with limited systemic exposure and side effect. However, sustained clinical benefits require long-term and multidimensional immune activation including innate and adaptive immunity. Here, we develop a probiotic food-grade Lactococcus lactis-based in situ vaccination (FOLactis) expressing a fusion protein of Fms-like tyrosine kinase 3 ligand and co-stimulator OX40 ligand. Intratumoural delivery of FOLactis contributes to local retention and sustained release of therapeutics to thoroughly modulate key components of the antitumour immune response, such as activation of natural killer cells, cytotoxic T lymphocytes, and conventional-type-1-dendritic cells in the tumors and tumor-draining lymph nodes. In addition, intratumoural administration of FOLactis induces a more robust tumor antigen-specific immune response and superior systemic antitumour efficacy in multiple poorly immune cell-infiltrated and anti-PD1-resistant tumors. Specific depletion of different immune cells reveals that CD8+ T and natural killer cells are crucial to the in situ vaccine-elicited tumor regression. Our results confirm that FOLactis displays an enhanced antitumour immunity and successfully converts the 'cold' tumors to 'hot' tumors. The probiotic Lactococcus lactis has been used for the delivery of therapeutic molecules. Here the authors engineer Lactococcus lactis to express a fusion protein of Flt3L and OX40 ligand, eliciting anti-tumor immune response in preclinical cancer models. [ABSTRACT FROM AUTHOR]

Despite recent advances in cancer immunotherapy, certain tumor types, such as Glioblastomas, are highly resistant due to their tumor microenvironment disabling the anti-tumor immune response. Here we show, by applying an in-silico multidimensional model integrating spatially resolved and single-cell gene expression data of 45,615 immune cells from 12 tumor samples, that a subset of Interleukin-10-releasing HMOX1+ myeloid cells, spatially localizing to mesenchymal-like tumor regions, drive T-cell exhaustion and thus contribute to the immunosuppressive tumor microenvironment. These findings are validated using a human ex-vivo neocortical glioblastoma model inoculated with patient derived peripheral T-cells to simulate the immune compartment. This model recapitulates the dysfunctional transformation of tumor infiltrating T-cells. Inhibition of the JAK/STAT pathway rescues T-cell functionality both in our model and in-vivo, providing further evidence of IL-10 release being an important driving force of tumor immune escape. Our results thus show that integrative modelling of single cell and spatial transcriptomics data is a valuable tool to interrogate the tumor immune microenvironment and might contribute to the development of successful immunotherapies. The tumour microenvironment counteracts immune therapy in Glioblastomas. Authors show here, using spatially resolved and single cell transcriptomics, that dysfunctional T cells are induced by a myeloid cell subset via Interleukin-10 signalling, and inhibition of the downstream JAK/STAT pathway might restore glioblastoma immune therapy responsiveness. [ABSTRACT FROM AUTHOR]

Helper (CD4+) T cells perform direct therapeutic functions and augment responses of cells such as cytotoxic (CD8+) T cells against a wide variety of diseases and pathogens. Nevertheless, inefficient synthetic technologies for expansion of antigen-specific CD4+ T cells hinders consistency and scalability of CD4+ T cell-based therapies, and complicates mechanistic studies. Here we describe a nanoparticle platform for ex vivo CD4+ T cell culture that mimics antigen presenting cells (APC) through display of major histocompatibility class II (MHC II) molecules. When combined with soluble co-stimulation signals, MHC II artificial APCs (aAPCs) expand cognate murine CD4+ T cells, including rare endogenous subsets, to induce potent effector functions in vitro and in vivo. Moreover, MHC II aAPCs provide help signals that enhance antitumor function of aAPC-activated CD8+ T cells in a mouse tumor model. Lastly, human leukocyte antigen class II-based aAPCs expand rare subsets of functional, antigen-specific human CD4+ T cells. Overall, MHC II aAPCs provide a promising approach for harnessing targeted CD4+ T cell responses. Adoptive cell therapies (ACT) hold promise for cancer immunotherapy, but optimization is still an ongoing process. Here the authors report CD4-targeted, nanoparticle-based artificial antigen-presenting cells that expand CD4+ T cells capable of lysing tumor cell lysis in vitro, and CD8+ T cells showing antitumor activity in a mouse melanoma model. [ABSTRACT FROM AUTHOR]

The SARS-CoV-2 Omicron variant has more than 15 mutations in the receptor binding domain of the Spike protein enabling increased transmissibility and viral escape from antibodies in vaccinated individuals. It is unclear how vaccine immunity protects against Omicron infection. Here we show that vaccinated participants at a super-spreader event have robust recall response of humoral and pre-existing cellular immunity induced by the vaccines, and an emergent de novo T cell response to non-Spike antigens. Individuals with Omicron SARS-CoV-2 breakthrough infections have significantly increased activated SARS-CoV-2 wild type Spike-specific cytotoxic T cells, activated follicular helper (TFH) cells, functional T cell responses, boosted humoral responses, and rapid release of Spike and RBD-specific IgG+ B cell plasmablasts and memory B cells into circulation. Omicron breakthrough infection affords significantly increased de novo memory T cell responses to non-Spike viral antigens. Concerted T and B cell responses may provide durable and broad immunity. The SARS-CoV-2 Omicron variant possess many mutations within the receptor binding domain of the Spike protein, which confer increased transmissibility and higher antibody escape. Here, the authors carry out analysis of the serological and cellular immune responses of individuals with Omicron breakthrough infection. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) suppress immune responses and thus contribute to immune homeostasis. On the downside, Tregs also limit immune responses against tumors promoting the progression of cancer. Among the many mechanisms implied in Treg-mediated suppression, the inhibition of dendritic cells (DCs) has been shown to be central in peripheral tolerance induction as well as in cancers. We have shown previously that the maintenance of peripheral T cell tolerance critically depends on cognate interactions between Tregs and DCs and that the CTL priming by unsuppressed steady state DCs is mediated via CD70. Here, we have investigated whether the CD70/CD27 axis is also involved in Treg-mediated suppression of anti-tumor immunity. Using a mixed bone marrow chimeric mouse model in which we can deplete regulatory T cells in a temporally controlled fashion, we show that Treg-expressed CD27 prevents the breakdown of peripheral tolerance and limits anti-tumor immunity. Furthermore, ablation of Treg expressed CD27 acts synergistically with PD-1 checkpoint inhibition to improve CTL mediated immunity against a solid tumor. Our data thus identify Treg-expressed CD27 as a potential target in cancer immunotherapy. Key messages: Treg expressed CD27 maintains steady state DC tolerogenic Treg expressed CD27 limits anti-tumor immunity Ablation of Treg expressed CD27 synergizes with PD-1 blockade to improve CTL mediated tumor control [ABSTRACT FROM AUTHOR]

Microsatellite-instable (MSI), a predictive biomarker for immune checkpoint blockade (ICB) response, is caused by mismatch repair deficiency (MMRd) that occurs through genetic or epigenetic silencing of MMR genes. Here, we report a mechanism of MMRd and demonstrate that protein phosphatase 2A (PP2A) deletion or inactivation converts cold microsatellite-stable (MSS) into MSI tumours through two orthogonal pathways: (i) by increasing retinoblastoma protein phosphorylation that leads to E2F and DNMT3A/3B expression with subsequent DNA methylation, and (ii) by increasing histone deacetylase (HDAC)2 phosphorylation that subsequently decreases H3K9ac levels and histone acetylation, which induces epigenetic silencing of MLH1. In mouse models of MSS and MSI colorectal cancers, triple-negative breast cancer and pancreatic cancer, PP2A inhibition triggers neoantigen production, cytotoxic T cell infiltration and ICB sensitization. Human cancer cell lines and tissue array effectively confirm these signaling pathways. These data indicate the dual involvement of PP2A inactivation in silencing MLH1 and inducing MSI. Microsatellite instability (MSI), caused by deficiency of the DNA mismatch repair system, has been associated with improved response to immune checkpoint blockade (ICB). Here the authors show that inactivation of protein phosphatase 2A induces a MSI status, promoting cytotoxic T cell infiltration and response to ICB in pre-clinical cancer models. [ABSTRACT FROM AUTHOR]

Adeno-associated virus (AAV)-mediated CRISPR-Cas9 editing holds promise to treat many diseases. The immune response to bacterial-derived Cas9 has been speculated as a hurdle for AAV-CRISPR therapy. However, immunological consequences of AAV-mediated Cas9 expression have thus far not been thoroughly investigated in large mammals. We evaluate Cas9-specific immune responses in canine models of Duchenne muscular dystrophy (DMD) following intramuscular and intravenous AAV-CRISPR therapy. Treatment results initially in robust dystrophin restoration in affected dogs but also induces muscle inflammation, and Cas9-specific humoral and cytotoxic T-lymphocyte (CTL) responses that are not prevented by the muscle-specific promoter and transient prednisolone immune suppression. In normal dogs, AAV-mediated Cas9 expression induces similar, though milder, immune responses. In contrast, other therapeutic (micro-dystrophin and SERCA2a) and reporter (alkaline phosphatase, AP) vectors result in persistent expression without inducing muscle inflammation. Our results suggest Cas9 immunity may represent a critical barrier for AAV-CRISPR therapy in large mammals. The Cas9-specific T cell response has been speculated to impair CRISPR therapy. Here, the authors show that local and systemic AAV CRISPR therapy induces cytotoxic killing and eliminates rescued dystrophin in canine models of Duchenne muscular dystrophy. [ABSTRACT FROM AUTHOR]

Presence of TGFβ in the tumor microenvironment is one of the most relevant cancer immune-escape mechanisms. TGFβ is secreted in an inactive form, and its activation within the tumor may depend on different cell types and mechanisms than its production. Here we show in mouse melanoma and breast cancer models that regulatory T (Treg) cells expressing the β8 chain of αvβ8 integrin (Itgβ8) are the main cell type in the tumors that activates TGFβ, produced by the cancer cells and stored in the tumor micro-environment. Itgβ8 ablation in Treg cells impairs TGFβ signalling in intra-tumoral T lymphocytes but not in the tumor draining lymph nodes. Successively, the effector function of tumor infiltrating CD8+ T lymphocytes strengthens, leading to efficient control of tumor growth. In cancer patients, anti-Itgβ8 antibody treatment elicits similar improved cytotoxic T cell activation. Thus, this study reveals that Treg cells work in concert with cancer cells to produce bioactive-TGFβ and to create an immunosuppressive micro-environment. TGFβ is secreted in an inactive form in the tumor microenvironment. Authors here show that although TGFβ is produced mainly by cancer cells, regulatory T cells are necessary for its activation via expression of the b8 chain of avb8 integrin. Thus, both cell types contribute to TGFβ dependent tumor growth. [ABSTRACT FROM AUTHOR]