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In the tumor microenvironment (TME), tumor cells are constantly evolving to reduce neoantigen generation and the mutational burden to escape the anti-tumor response. This will lower tumor reactivity to the adaptive immune response and give rise to tumor intrinsic factors, such as altered expression of immune regulatory molecules on tumor cells. Tumor-extrinsic factors, such as immunosuppressive cells, soluble suppressive molecules or inhibitory receptors expressed by immune cells will alter the composition and activity of tumor-infiltrating lymphocytes (TILs) (by increasing T regulatory cells:T effector cells ratio and inhibiting T effector cell function) and promote tumor growth and metastasis. Together, these factors limit the response rates and clinical outcomes to a particular cancer therapy. Within the TME, the cross-talks between immune and non-immune cells result in the generation of positive feedback loops, which augment immunosuppression and support tumor growth and survival (termed as tumor-mediated immunosuppression). Cancer immunotherapies, such as immune checkpoint inhibitors (ICIs) and adoptive cell transfer (ACT), have shown therapeutic efficacy in hematologic cancers and different types of solid tumors. However, achieving durable response rates in some cancer patients remains a challenge as a result of acquired resistance and tumor immune evasion. This could be driven by the cellular and molecular suppressive network within the TME or due to the loss of tumor antigens. In this review, we describe the contribution of the immunosuppressive cellular and molecular tumor network to the development of acquired resistance against cancer immunotherapies. We also discuss potential combined therapeutic strategies which could help to overcome such resistance against cancer immunotherapies, and to enhance anti-tumor immune responses and improve clinical outcomes in patients. [ABSTRACT FROM AUTHOR]

Exhaustion of immune cells in COVID-19 remains a serious concern for infection management and therapeutic interventions. As reported, immune cells such as T effector cells (Teff), T regulatory cells (Tregs), natural killer cells (NKs), and antigen-presenting cells (APCs) exhibit uncontrolled functions in COVID-19. Unfortunately, the mechanisms that orchestrate immune cell functionality and virus interaction are still unknown. Recent studies linked adaptive immune cell exhaustion to underlying epigenetic mechanisms that regulate the epigenetic transcription of inhibitory immune checkpoint receptors (ICs). Further to that, the over-activation of T cells accompanied by the dysfunctionality of DCs and Tregs may enhance uncontrollable alveoli inflammation and cytokine storm in COVID-19. This might explain the reasons behind the failure of DC-based vaccines in inducing sufficient anti-viral responses. This review explains the processes behind the over-activation and exhaustion of innate and adaptive immune cells in COVID-19, which may contribute to developing novel immune intervention strategies. • Overexpression of ICs and mitochondrial impairment in T cells contribute to increasing the severity of COVID-19. • T cell Exhaustion is caused primarily by ICs overexpression, even in low cytokine-producing T cells. • Over-activation of T cells in COVID-19 may elicit epithelial cell apoptosis and cytokine storm initiation. • SARS-CoV-2 promotes ICs upregulation by increasing epigenetic chromatin accessibility and ICs transcription. • Interaction between SARS-CoV-2 ORF8/ORF6 proteins and MHCI/II promotes the exhaustion of cytotoxic immune cells. [ABSTRACT FROM AUTHOR]

Abstract: Conversion of conventional T cells into T regulatory cells (Tregs) has been proposed as a potential mechanism for Treg expansion in cancer. However, this evidence is supported by in vitro or mouse model studies with no data from in vivo or human studies to support its role in enriching peripheral and tumor-infiltrating Tregs. Recent work has shown that induced FoxP3+ Tregs (iTregs) do not express Helios; an Ikaros family transcription factor. We analyzed peripheral blood samples from untreated renal cell carcinoma (RCC) patients and following interleukin (IL)-2 treatment for the expression of FoxP3 and Helios. Our work shows that expanded peripheral FoxP3+ Tregs in untreated RCC patients co-express Helios. Interestingly, IL-2 administration results in expansion of FoxP3+Helios+ natural Tregs (nTregs) significantly more than FoxP3+Helios− iTregs. Our work shows that the increased FoxP3+ Treg subpopulation in RCC patients co-express Helios, indicating that they could be derived from natural but not induced Tregs. [Copyright &y& Elsevier]

Abstract: Modest work has been performed to improve the sensitivity of residual disease detection or investigate the contribution that the immune system makes in controlling metastatic tumor growth, in particular, the frequency and biological actions of peptide-specific CD8+ T lymphocytes in limiting metastatic disease and/or maintaining remission. Fifty-three peripheral blood samples from 32 prostate cancer (PC) patients were investigated for the presence of circulating prostate-specific antigen (PSA)-expressing cells (CPECs) using a highly sensitive and specific assay combining immunomagnetic epithelial cell enrichment with nested RT-PCR of PSA mRNA. Using HLA-A2 tetramer complexes, frequency of CD8+ T cells specific for PSA-derived peptides was determined. Additionally, serum concentrations of PSA and testosterone were measured. CPECs were detected in 26% of peripheral blood samples from PC patients. CD8+ T cells specific for PSA-derived peptides were detected at low frequency in HLA-A2-positive PC patients. The correlation between these PSA-specific CD8+ T cells and residual prostate tumor cells and clinical measures was investigated. Our data suggest that frequency of PSA-specific CD8+ T cells is correlated to CPECs, but not to serum PSA level. [Copyright &y& Elsevier]

Interactions between immune checkpoints (ICs) and their ligands negatively regulate T cell activation pathways involved in physiological immune responses against specific antigens. ICs and their ligands are frequently upregulated in the tumor microenvironment (TME) of various malignancies, and they represent significant barriers for induction of effective anti-tumor immune responses. Several IC inhibitors (ICIs) have been developed, with some currently in clinical trials and others have been approved for the treatment of different cancers. However, tumor cells are able to counteract the activity of ICIs and can commission additional inhibitory pathways via expression of other ICs/ligands within the TME. This review discusses the expression of various ICs/ligands in the TME and their impact on tumor immune evasion. Additionally, we discuss various regulatory mechanisms, including genetic and epigenetic, and other modulatory factors including hypoxia and the presence of immunosuppressive populations in the TME, which result in upregulation of ICs in various cancers. Moreover, we discuss the prognostic significance of ICs and their ligands, and the potential strategies to enhance treatment responses to ICIs. This review aims to advance our current knowledge on the role of ICs in the TME and the clinical benefits of targeting them. [ABSTRACT FROM AUTHOR]

Abstract: Cytotoxic T Lymphocyte Antigen 4 (CTLA4) blockade has shown antitumor activity against common cancers. However, the exact mechanism of immune mediation by anti-CTLA4 remains to be elucidated. Further understanding of how CTLA4 blockade with tremelimumab mediates immune responses may allow a more effective selection of responsive patients. Our results show that tremelimumab enhanced the proliferative response of T effector cells (Teff) upon TCR stimulation, and abrogated Treg suppressive ability. In the presence of tremelimumab, frequencies of IL-2-secreting CD4+ T cells and IFN-γ-secreting CD4+ and CD8+ T cells were increased in response to polyclonal activation and tumor antigens. Importantly, Treg frequency was not reduced in the presence of tremelimumab, and expanded Tregs in cancer patients treated with tremelimumab expressed FoxP3 with no IL-2 release, confirming them as bona fide Tregs. Taken together, this data indicates that tremelimumab induces immune responses mainly by direct activation of Teff rather than by affecting Tregs. [ABSTRACT FROM AUTHOR]

T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) is an inhibitory immune checkpoint, which suppresses anti-tumor immune responses. TIM-3 expression on different immune cells in periphery and tumor microenvironment (TME) of colorectal cancer (CRC) patients has not been fully investigated. We found that TIM-3 was mainly expressed on monocytic myeloid cells (MMCs) and antigen-presenting cells (APCs) in circulation but was mainly expressed on T cells and APCs in the TME. Additionally, TIM-3− T cells co-expressed higher levels of PD-1 than TIM-3+ T cells in normal tissue. In contrast, TIM-3+ T cells in the TME showed significantly higher PD-1 expression. Interestingly, there was a trend towards increased levels of TIM-3+ APCs with disease stages; however, levels of TIM-3+ T cells were decreased with disease stages in the TME. This study shows the differential expression of TIM-3 on different immune cells in circulation and TME of CRC patients, and their associations with disease stages. • High TIM-3 expression in CRC warrants characterization on immune cell populations. • TIM-3 was mainly expressed on MMCs and APCs in blood, APCs and T cells in the TME. • Unlike normal tissue, TIM-3 was co-expressed with PD-1 in tumor-infiltrating T cells. • There was a trend towards increased levels of TIM-3+ APCs with disease stages. • Levels of TIM-3+ T cells were decreased with disease stages in the TME. [ABSTRACT FROM AUTHOR]

Cancer immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Although considerable progress has been made in understanding how cancers evade destructive immunity, measures to counteract tumor escape have not kept pace. There are a number of factors that contribute to tumor persistence despite having a normal host immune system. Immune editing is one of the key aspects why tumors evade surveillance causing the tumors to lie dormant in patients for years through “equilibrium” and “senescence” before re-emerging. In addition, tumors exploit several immunological processes such as targeting the regulatory T cell function or their secretions, antigen presentation, modifying the production of immune suppressive mediators, tolerance and immune deviation. Besides these, tumor heterogeneity and metastasis also play a critical role in tumor growth. A number of potential targets like promoting Th1, NK cell, γδ T cell responses, inhibiting Treg functionality, induction of IL-12, use of drugs including phytochemicals have been designed to counter tumor progression with much success. Some natural agents and phytochemicals merit further study. For example, use of certain key polysaccharide components from mushrooms and plants have shown to possess therapeutic impact on tumor-imposed genetic instability, anti-growth signaling, replicative immortality, dysregulated metabolism etc. In this review, we will discuss the advances made toward understanding the basis of cancer immune evasion and summarize the efficacy of various therapeutic measures and targets that have been developed or are being investigated to enhance tumor rejection. [ABSTRACT FROM AUTHOR]