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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]

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]

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]

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]

T-cell intracellular antigen 1 (TIA1)-related/like (TIAR/TIAL1) protein is a multifunctional RNA-binding protein (RBP) involved in regulating many aspects of gene expression, independently or in combination with its paralog TIA1. TIAR was first described in 1992 by Paul Anderson's lab in relation to the development of a cell death phenotype in immune system cells, as it possesses nucleolytic activity against cytotoxic lymphocyte target cells. Similar to TIA1, it is characterized by a subcellular nucleo-cytoplasmic localization and ubiquitous expression in the cells of different tissues of higher organisms. In this paper, we review the relevant structural and functional information available about TIAR from a triple perspective (molecular, cellular and pathophysiological), paying special attention to its expression and regulation in cellular events and processes linked to human pathophysiology. [ABSTRACT FROM AUTHOR]

In this paper, a deterministic model characterizing the within-host infection of Hepatitis C virus (HCV) in intrahepatic and extrahepatic tissues is presented. In addition, the model also includes the effect of the cytotoxic T lymphocyte (CTL) immunity described by a linear activation rate by infected cells. Firstly, the non-negativity and boundedness of solutions of the model are established. Secondly, the basic reproduction number R 01 and immune reproduction number R 02 are calculated, respectively. Three equilibria, namely, infection-free, CTL immune response-free and infected equilibrium with CTL immune response are discussed in terms of these two thresholds. Thirdly, the stability of these three equilibria is investigated theoretically as well as numerically. The results show that when R 01 < 1 , the virus will be cleared out eventually and the CTL immune response will also disappear; when R 02 < 1 < R 01 , the virus persists within the host, but the CTL immune response disappears eventually; when R 02 > 1 , both of the virus and the CTL immune response persist within the host. Finally, a brief discussion will be given. [ABSTRACT FROM AUTHOR]

Despite many recent advances on cancer novel therapies, researchers have yet a long way to cure cancer. They have to deal with tough challenges before they can reach success. Nonetheless, it seems that recently developed immunotherapy-based therapy approaches such as adoptive cell transfer (ACT) have emerged as a promising therapeutic strategy against various kinds of tumors even the cancers in the blood (liquid cancers). The hematological (liquid) cancers are hard to be targeted by usual cancer therapies, for they do not form localized solid tumors. Until recently, two types of ACTs have been developed and introduced; tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR)-T cells which the latter is the subject of our discussion. It is interesting about engineered CAR-T cells that they are genetically endowed with unique cancer-specific characteristics, so they can use the potency of the host immune system to fight against either solid or liquid cancers. Multiple myeloma (MM) or simply referred to as myeloma is a type of hematological malignancy that affects the plasma cells. The cancerous plasma cells produce immunoglobulins (antibodies) uncontrollably which consequently damage the tissues and organs and break the immune system function. Although the last few years have seen significant progressions in the treatment of MM, still a complete remission remains unconvincing. MM is a medically challenging and stubborn disease with a disappointingly low rate of survival rate. When comparing the three most occurring blood cancers (i.e., lymphoma, leukemia, and myeloma), myeloma has the lowest 5-year survival rate (around 40%). A low survival rate indicates a high mortality rate with difficulty in treatment. Therefore, novel CAR-T cell-based therapies or combination therapies along with CAT-T cells may bring new hope for multiple myeloma patients. CAR-T cell therapy has a high potential to improve the remission success rate in patients with MM. To date, many preclinical and clinical trial studies have been conducted to investigate the ability and capacity of CAR T cells in targeting the antigens on myeloma cells. Despite the problems and obstacles, CAR-T cell experiments in MM patients revealed a robust therapeutic potential. However, several factors might be considered during CAR-T cell therapy for better response and reduced side effects. Also, incorporating the CAT-T cell method into a combinational treatment schedule may be a promising approach. In this paper, with a greater emphasis on CAR-T cell application in the treatment of MM, we will discuss and introduce CAR-T cell's history and functions, their limitations, and the solutions to defeat the limitations and different types of modifications on CAR-T cells. [ABSTRACT FROM AUTHOR]

Despite many recent advances on cancer novel therapies, researchers have yet a long way to cure cancer. They have to deal with tough challenges before they can reach success. Nonetheless, it seems that recently developed immunotherapy-based therapy approaches such as adoptive cell transfer (ACT) have emerged as a promising therapeutic strategy against various kinds of tumors even the cancers in the blood (liquid cancers). The hematological (liquid) cancers are hard to be targeted by usual cancer therapies, for they do not form localized solid tumors. Until recently, two types of ACTs have been developed and introduced; tumor-infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR)-T cells which the latter is the subject of our discussion. It is interesting about engineered CAR-T cells that they are genetically endowed with unique cancer-specific characteristics, so they can use the potency of the host immune system to fight against either solid or liquid cancers. Multiple myeloma (MM) or simply referred to as myeloma is a type of hematological malignancy that affects the plasma cells. The cancerous plasma cells produce immunoglobulins (antibodies) uncontrollably which consequently damage the tissues and organs and break the immune system function. Although the last few years have seen significant progressions in the treatment of MM, still a complete remission remains unconvincing. MM is a medically challenging and stubborn disease with a disappointingly low rate of survival rate. When comparing the three most occurring blood cancers (i.e., lymphoma, leukemia, and myeloma), myeloma has the lowest 5-year survival rate (around 40%). A low survival rate indicates a high mortality rate with difficulty in treatment. Therefore, novel CAR-T cell-based therapies or combination therapies along with CAT-T cells may bring new hope for multiple myeloma patients. CAR-T cell therapy has a high potential to improve the remission success rate in patients with MM. To date, many preclinical and clinical trial studies have been conducted to investigate the ability and capacity of CAR T cells in targeting the antigens on myeloma cells. Despite the problems and obstacles, CAR-T cell experiments in MM patients revealed a robust therapeutic potential. However, several factors might be considered during CAR-T cell therapy for better response and reduced side effects. Also, incorporating the CAT-T cell method into a combinational treatment schedule may be a promising approach. In this paper, with a greater emphasis on CAR-T cell application in the treatment of MM, we will discuss and introduce CAR-T cell's history and functions, their limitations, and the solutions to defeat the limitations and different types of modifications on CAR-T cells. [ABSTRACT FROM AUTHOR]

In the literature, several mathematical models have been formulated and developed to describe the within-host dynamics of either human immunodeficiency virus (HIV) or human T-lymphotropic virus type I (HTLV-I) monoinfections. In this paper, we formulate and analyze a novel within-host dynamics model of HTLV-HIV coinfection taking into consideration the response of cytotoxic T lymphocytes (CTLs). The uninfected CD 4 + T cells can be infected via HIV by two mechanisms, free-to-cell and infected-to-cell. On the other hand, the HTLV-I has two modes for transmission, (i) horizontal, via direct infected-to-cell touch, and (ii) vertical, by mitotic division of active HTLV-infected cells. It is well known that the intracellular time delays play an important role in within-host virus dynamics. In this work, we consider six types of distributed-time delays. We investigate the fundamental properties of solutions. Then, we calculate the steady states of the model in terms of threshold parameters. Moreover, we study the global stability of the steady states by using the Lyapunov method. We conduct numerical simulations to illustrate and support our theoretical results. In addition, we discuss the effect of multiple time delays on stability of the steady states of the system. [ABSTRACT FROM AUTHOR]

Immunotherapy is considered as an effective method for cancer treatment owing to the induction of specific and long-lasting anti-cancer effects. Immunotherapeutic strategies have shown significant success in human malignancies, particularly in prostate cancer (PCa), a major global health issue regarding its high metastatic rates. In fact, the first cancer vaccine approved by FDA was Provenge, which has been successfully used for treatment of PCa. Despite the remarkable success of cancer immunotherapy in PCa, many of the developed immunotherapy methods show poor therapeutic outcomes. Immunosuppression in tumor microenvironment (TME) induced by non-functional T cells (CD4+ and CD8+), tolerogenic dendritic cells (DCs), and regulatory T cells, has been reported to be the main obstacle to the effectiveness of anti-tumor immune responses induced by an immunotherapy method. The present review particularly focuses on the latest findings of the immune checkpoints (ICPs), including CTLA-4, PD-1, PD-L1, LAG-3, OX40, B7-H3, 4-1BB, VISTA, TIM-3, and ICOS; these checkpoints are able to have immune modulatory effects on the TME of PCa. This paper further discusses different approaches in ICPs targeting therapy and summarizes the latest advances in the clinical application of ICP-targeted therapy as monotherapy or in combination with other cancer therapy modalities in PCa. [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]

Many mRNA-based vaccines have been investigated for their specific potential to activate dendritic cells (DCs), the highly-specialized antigen-presenting cells of the immune system that play a key role in inducing effective CD4+ and CD8+ T-cell responses. In this paper we report a new vaccine/gene delivery platform that demonstrates the benefits of using a self-amplifying (“replicon”) mRNA that is protected in a viral-protein capsid. Purified capsid protein from the plant virus Cowpea Chlorotic Mottle Virus (CCMV) is used to in vitro assemble monodisperse virus-like particles (VLPs) containing reporter proteins (e.g., Luciferase or eYFP) or the tandem-repeat model antigen SIINFEKL in RNA gene form, coupled to the RNA-dependent RNA polymerase from the Nodamura insect virus. Incubation of immature DCs with these VLPs results in increased activation of maturation markers – CD80, CD86 and MHC-II – and enhanced RNA replication levels, relative to incubation with unpackaged replicon mRNA. Higher RNA uptake/replication and enhanced DC activation were detected in a dose-dependent manner when the CCMV-VLPs were pre-incubated with anti-CCMV antibodies. In all experiments the expression of maturation markers correlates with the RNA levels of the DCs. Overall, these studies demonstrate that: VLP protection enhances mRNA uptake by DCs; coupling replicons to the gene of interest increases RNA and protein levels in the cell; and the presence of anti-VLP antibodies enhances mRNA levels and activation of DCs in vitro. Finally, preliminary in vivo experiments involving mouse vaccinations with SIINFEKL-replicon VLPs indicate a small but significant increase in antigen-specific T cells that are doubly positive for IFN and TFN induction. [ABSTRACT FROM AUTHOR]

Oncolytic virus (OV) is a replication competent virus that selectively invades cancer cells; as these cells die under the viral burden, the released virus particles proceed to infect other cancer cells. Oncolytic viruses are designed to also be able to stimulate the anticancer immune response. Thus, one may represent an OV by two parameters: its replication potential and its immunogenicity. In this paper we consider a combination therapy with OV and a checkpoint inhibitor, anti-PD-1. We evaluate the efficacy of the combination therapy in terms of the tumor volume at some later time, for example, 6 months from initial treatment. Since T cells kill not only virus-free cancer cells but also virus-infected cancer cells, the following question arises: Does increasing the amount of the checkpoint inhibitor always improve the efficacy? We address this question, by a mathematical model consisting of a system of partial differential equations. We use the model to construct, by simulations, an efficacy map in terms of the doses of the checkpoint inhibitor and the OV injection. We show that there are regions in the map where an increase in the checkpoint inhibitor actually decreases the efficacy of the treatment. We also construct efficacy maps with checkpoint inhibitor vs. the replication potential of the virus that show the same antagonism, namely, an increase in the checkpoint inhibitor may actually decrease the efficacy. These results have implications for clinical trials. [ABSTRACT FROM AUTHOR]

Cross-presentation of apoptotic cell associated antigens by immature dendritic cells prevents the activation of self reactive CD8 T cells. Tolerized self reactive CD8 T cells down-regulate IL-7R expression on their surface. Whether over-expression of IL-7R can reverse their fate and function has not been examined. In this paper, we showed forced expression of IL-7R in OT-I T cells by a transgene enhanced CD8 T cell mediated diabetes in the RIP-mOVA model. Although IL-7R Tg (transgenic) did not completely reverse the deletion of OT-I T cells, it provided a significant survival advantage over w.t OT-I T cells. Furthermore, IL7R Tg OT-I T cells isolated from diabetic pancreata displayed increased production of IFN-γ, higher expression of T-bet, and increased externalization of CD107a. We also found that immature DCs containing apoptotic cells expressed high levels of PDL-1 on their surface. Although IL-7R Tg did not change PD1 expression on activated OT-I cells in vivo, the transgene enabled a significantly lower number of OT-I T cells to induce diabetes in the absence of PDL-1. Our results demonstrated that forced expression of IL-7R not only improved the functionality of tolerized CD8 T cells, it also acted in synergy with PDL-1 deficiency to further promote CD8 T cell cytotoxicity to self antigens. [ABSTRACT FROM AUTHOR]

In this paper we consider a combination therapy of cancer. One drug is a vaccine which activates dendritic cells so that they induce more T cells to infiltrate the tumor. The other drug is a checkpoint inhibitor, which enables the T cells to remain active against the cancer cells. The two drugs are positively correlated in the sense that an increase in the amount of each drug results in a reduction in the tumor volume. We consider the question whether a treatment with combination of the two drugs at certain levels is preferable to a treatment by one of the drugs alone at ‘roughly’ twice the dosage level; if that is the case, then we say that there is a positive ‘synergy’ for this combination of dosages. To address this question, we develop a mathematical model using a system of partial differential equations. The variables include dendritic and cancer cells, CD4+ and CD8+ T cells, IL-12 and IL-2, GM-CSF produced by the vaccine, and a T cell checkpoint inhibitor associated with PD-1. We use the model to explore the efficacy of the two drugs, separately and in combination, and compare the simulations with data from mouse experiments. We next introduce the concept of synergy between the drugs and develop a synergy map which suggests in what proportion to administer the drugs in order to achieve the maximum reduction of tumor volume under the constraint of maximum tolerated dose. [ABSTRACT FROM AUTHOR]

Experimental and mathematical studies in immunology have revealed that the dynamics of the programmed T cell response to vigorous infection can be conveniently modelled using a sigmoidal or a discontinuous immune response function. This paper hypothesizes strong synergies between this existing work and the dynamical behaviour of engineering systems with a variable structure control (VSC) law. These findings motivate the interpretation of the immune system as a variable structure control system. It is shown that dynamical properties as well as conditions to analytically assess the transition from health to disease can be developed for the specific T cell response from the theory of variable structure control. In particular, it is shown that the robustness properties of the specific T cell response as observed in experiments can be explained analytically using a VSC perspective. Further, the predictive capacity of the VSC framework to determine the T cell help required to overcome chronic Lymphocytic Choriomeningitis Virus (LCMV) infection is demonstrated. The findings demonstrate that studying the immune system using variable structure control theory provides a new framework for evaluating immunological dynamics and experimental observations. A modelling and simulation tool results with predictive capacity to determine how to modify the immune response to achieve healthy outcomes which may have application in drug development and vaccine design. [ABSTRACT FROM AUTHOR]

This paper distinguishes a rare subset of myeloid dendritic-like cells found in mouse spleen from conventional (c) dendritic cells (DC) in terms of phenotype, function and gene expression. These cells are tentatively named “L-DC” since they resemble dendritic-like cells produced in longterm cultures of spleen. L-DC can be distinguished on the basis of their unique phenotype as CD11bhiCD11cloMHCII-CD43+Ly6C-Ly6G-Siglec-F- cells. They demonstrate similar ability as cDC to uptake and retain complex antigens like mannan via mannose receptors, but much lower ability to endocytose and retain soluble antigen. While L-DC differ from cDC by their inability to activate CD4+ T cells, they are capable of antigen cross-presentation for activation of CD8+ T cells, although less effectively so than the cDC subsets. In terms of gene expression, CD8- cDC and CD8+ cDC are quite distinct from L-DC. CD8+ cDC are distinguishable from the other two subsets by expression of CD24a, Clec9a, Xcr1 and Tlr11, while CD8- cDC are distinguished by expression of Ccnd1 and H-2Eb2. L-DC are distinct from the two cDC subsets through upregulated expression of Clec4a3, Emr4, Itgam, Csf1r and CD300ld. The L-DC gene profile is quite distinct from that of cDC, confirming a myeloid cell type with distinct antigen presenting properties. [ABSTRACT FROM AUTHOR]

During early human immunodeficiency virus (HIV) infection multiple CD8+ T cell responses are elicited almost simultaneously. These responses exert strong selective pressures on different parts of HIV’s genome, and select for mutations that escape recognition and are thus beneficial to the virus. Some studies reveal that the later these escape mutations emerge, the more slowly they go to fixation. This pattern of escape rate decrease(ERD) can arise by distinct mechanisms. In particular, in large populations with high beneficial mutation rates interference among different escape strains –an effect that can emerge in evolution with asexual reproduction and results in delayed fixation times of beneficial mutations compared to sexual reproduction– could significantly impact the escape rates of mutations. In this paper, we investigated how interference between these concurrent escape mutations affects their escape rates in systems with multiple epitopes, and whether it could be a source of the ERD pattern. To address these issues, we developed a multilocus Wright-Fisher model of HIV dynamics with selection, mutation and recombination, serving as a null-model for interference. We also derived an interference-free null model assuming initial neutral evolution before immune response elicitation. We found that interference between several equally selectively advantageous mutations can generate the observed ERD pattern. We also found that the number of loci, as well as recombination rates substantially affect ERD. These effects can be explained by the underexponential decline of escape rates over time. Lastly, we found that the observed ERD pattern in HIV infected individuals is consistent with both independent, interference-free mutations as well as interference effects. Our results confirm that interference effects should be considered when analyzing HIV escape mutations. The challenge in estimating escape rates and mutation-associated selective coefficients posed by interference effects cannot simply be overcome by improved sampling frequencies or sizes. This problem is a consequence of the fundamental shortcomings of current estimation techniques under interference regimes. Hence, accounting for the stochastic nature of competition between mutations demands novel estimation methodologies based on the analysis of HIV strains, rather than mutation frequencies. [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]

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia among adults. It is the clonal expansion of B cells expressing CD19 and CD5. Despite significant progress in treatment, CLL is still incurable. γδ T cells comprise an important subset of the cytotoxic T cells. Although γδ T cells in CLL are dysfunctional, they still can possibly be used for immunotherapy. The current paper reviews our understanding of γδ T lymphocytes in CLL. [ABSTRACT FROM AUTHOR]

Lack of immunogenicity of cancer cells has been considered a major reason for their failure in induction of a tumor specific T cell response. In this paper, we present evidence that decitabine (DAC), a DNA methylation inhibitor that is currently used for the treatment of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and other malignant neoplasms, is capable of eliciting an anti-tumor cytotoxic T lymphocyte (CTL) response in mouse EL4 tumor model. C57BL/6 mice with established EL4 tumors were treated with DAC (1.0 mg/kg body weight) once daily for 5 days. We found that DAC treatment resulted in infiltration of IFN-γ producing T lymphocytes into tumors and caused tumor rejection. Depletion of CD8+, but not CD4+ T cells resumed tumor growth. DAC-induced CTL response appeared to be elicited by the induction of CD80 expression on tumor cells. Epigenetic evidence suggests that DAC induces CD80 expression in EL4 cells via demethylation of CpG dinucleotide sites in the promoter of CD80 gene. In addition, we also showed that a transient, low-dose DAC treatment can induce CD80 gene expression in a variety of human cancer cells. This study provides the first evidence that epigenetic modulation can induce the expression of a major T cell co-stimulatory molecule on cancer cells, which can overcome immune tolerance, and induce an efficient anti-tumor CTL response. The results have important implications in designing DAC-based cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are inhibitory checkpoints that are commonly seen on activated T cells and have been offered as promising targets for the treatment of cancers. Immune checkpoint inhibitors (ICIs)targeting PD-1, including pembrolizumab and nivolumab, and those targeting its ligand PD-L1, including avelumab, atezolizumab, and durvalumab, and two drugs targeting CTLA-4, including ipilimumab and tremelimumab have been approved for the treatment of several cancers and many others are under investigating in advanced trial phases. ICIs increased antitumor T cells' responses and showed a key role in reducing the acquired immune system tolerance which is overexpressed by cancer and tumor microenvironment. However, 50% of patients could not benefit from ICIs monotherapy. To overcome this, a combination of ipilimumab and nivolumab is frequently investigated as an approach to improve oncological outcomes. Despite promising results for the combination of ipilimumab and nivolumab, safety concerns slowed down the development of such strategies. Herein, we review data concerning the clinical activity and the adverse events of ipilimumab and nivolumab combination therapy, assessing ongoing clinical trials to identify clinical outlines that may support combination therapy as an effective treatment. To the best of our knowledge, this paper is one of the first studies to evaluate the efficacy and safety of ipilimumab and nivolumab combination therapy in several cancers. [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]

Explosive growth in nanotechnology has merged with vaccine development in the battle against diseases caused by bacterial or viral infections and malignant tumors. Due to physicochemical characteristics including size, viscosity, density and electrostatic properties, nanomaterials have been applied to various vaccination strategies. Nanovaccines, as they are called, have been the subject of many studies, including review papers from a material science point of view, although a mode of action based on a biological and immunological understanding has yet to emerge. In this review, we discuss nanovaccines in terms of CD8+ T cell responses, which are essential for antiviral and anticancer therapies. We focus mainly on the role and mechanism, with particular attention to the functional aspects, of nanovaccines in inducing cross-presentation, an unconventional type of antigen-presentation that activates CD8+ T cells upon administration of exogenous antigens, in dendritic cells followed by activation of antigen-specific CD8+ T cell responses. Two major intracellular mechanisms that nanovaccines harness for cross-presentation are described; one is endosomal swelling and rupture, and the other is membrane fusion. Both processes eventually allow exogenous vaccine antigens to be exported from phagosomes to the cytosol followed by loading on major histocompatibility complex class I, triggering clonal expansion of CD8+ T cells. Advancement of nanotechnology with an enhanced understanding of how nanovaccines work will contribute to the design of more effective and safer nanovaccines. [ABSTRACT FROM AUTHOR]

Functional, tumor-specific CD8+ cytotoxic T lymphocytes drive the adaptive immune response to cancer. Thus, induction of their activity is the ultimate aim of all immunotherapies. Success of anti-tumor immunotherapy is precluded by marked immunosuppression in the tumor microenvironment (TME) leading to CD8+ effector T cell dysfunction. Among the many facets of CD8+ T cell dysfunction that have been recognized—tolerance, anergy, exhaustion, and senescence—CD8+ T cell senescence is incompletely understood. Naïve CD8+ T cells require three essential signals for activation, differentiation, and survival through T-cell receptor, costimulatory receptors, and cytokine receptors. Downregulation of costimulatory molecule CD28 is a hallmark of senescent T cells and increased CD8+CD28− senescent populations with heterogeneous roles have been observed in multiple solid and hematogenous tumors. T cell senescence can be induced by several factors including aging, telomere damage, tumor-associated stress, and regulatory T (Treg) cells. Tumor-induced T cell senescence is yet another mechanism that enables tumor cell resistance to immunotherapy. In this paper, we provide a comprehensive overview of CD8+CD28− senescent T cell population, their origin, their function in immunology and pathologic conditions, including TME and their implication for immunotherapy. Further characterization and investigation into this subset of CD8+ T cells could improve the efficacy of future anti-tumor immunotherapy. [ABSTRACT FROM AUTHOR]