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Gliomas are the most common primary brain tumors in adults. Despite the fact that they are relatively rare, they cause significant morbidity and mortality. High-grade gliomas or glioblastomas are rapidly progressing tumors with a very poor prognosis. The presence of an intrinsic immune system in the central nervous system is now more accepted. During the last decade, there has been no major progress in glioma therapy. The lack of effective treatment for gliomas can be explained by the strategies that cancer cells use to escape the immune system. This being said, immunotherapy, which involves blockade of immune checkpoint inhibitors, has improved patients’ survival in different cancer types. This novel cancer therapy appears to be one of the most promising approaches. In the present study, we will start with a review of the general concept of immune response within the brain and glioma microenvironment. Then, we will try to decipher the role of various immune checkpoint inhibitors within the glioma microenvironment. Finally, we will discuss some promising therapeutic pathways, including immune checkpoint blockade and the body’s effective anti-glioma immune response.

A randomized trial compared standard chemotherapy plus dostarlimab or placebo. Patients with mismatch repair–deficient tumors had 2-year progression-free survival of 61.4% with dostarlimab and 15.7% with placebo.

The immune system serves as a fundamental defender against the initiation and progression of cancer. Failure of the immune system augments immunosuppressive action that leading to cancer manifestation. This immunosuppressive effect causes from significant alterations in immune checkpoint expression associated with tumoral progression. The tumor microenvironment promotes immune escape mechanisms that further amplifying immunosuppressive actions. Notably, substantial targeting of immune checkpoints has been pragmatic in the advancement of cancer research. This study highlights a comprehensive review of emerging druggable targets aimed at modulating immune checkpoint co-inhibitory as well as co-stimulatory molecules in response to immune system activation. This modulation has prompted to the development of newer therapeutic insights, eventually inducing immunogenic cell death through immunomodulatory actions. The study emphasizes the role of immune checkpoints in immunogenic regulation of cancer pathogenesis and explores potential therapeutic avenues in cancer immunotherapy.Modulation of Immunosuppressive and Immunostimulatory pathways of immune checkpoints in cancer immunotherapy

Immunotherapy, with an increasing number of therapeutic dimensions, is becoming an important mode of treatment for cancer patients. The inhibition of immune checkpoints, which are the source of immune escape for various cancers, is one such immunotherapeutic dimension. It has mainly been aimed at T cells in the past, but NK cells are a newly emerging target. Simultaneously, the number of checkpoints identified has been increasing in recent times. In addition to the classical NK cell receptors KIRs, LIRs, and NKG2A, several other immune checkpoints have also been shown to cause dysfunction of NK cells in various cancers and chronic infections. These checkpoints include the revolutionized CTLA-4, PD-1, and recently identified B7-H3, as well as LAG-3, TIGIT & CD96, TIM-3, and the most recently acknowledged checkpoint-members of the Siglecs family (Siglec-7/9), CD200 and CD47. An interesting dimension of immune checkpoints is their candidacy for dual-checkpoint inhibition, resulting in therapeutic synergism. Furthermore, the combination of immune checkpoint inhibition with other NK cell cytotoxicity restoration strategies could also strengthen its efficacy as an antitumor therapy. Here, we have undertaken a comprehensive review of the literature to date regarding NK cell-based immune checkpoints.

Tumor cells form immune escape and subsequently obtain unlimited proliferation ability due to the abnormal immune surveillance mediated by immune checkpoints. Among this class of immune checkpoints, PD-1/PD-L1 was recognized as an anticancer drug target for many years, and so far, several monoclonal antibodies have achieved encouraging outcome in cancer treatment by targeting the PD-1/PD-L1 signaling pathway. Due to the inherent limitations of antibodies, the development of small molecule inhibitors based on PD-1/PD-L1 signaling pathway is gradually reviving in decades. In this review, we summarized a number of small molecule inhibitors based on three different therapeutic approaches interfering PD-1/PD-L1 signaling pathway: (1) blocking direct interaction between PD-1 and PD-L1; (2) inhibiting transcription and translation of PD-L1; and (3) promoting degradation of PD-L1 protein. The development of these small molecule inhibitors opens a new avenue for tumor immunotherapy based on PD-1/PD-L1 signaling pathway.

As a nontraditional T-cell subgroup, γδT cells have gained popularity in the field of immunotherapy in recent years. They have extraordinary antitumor potential and prospects for clinical application. Immune checkpoint inhibitors (ICIs), which are efficacious in tumor patients, have become pioneer drugs in the field of tumor immunotherapy since they were incorporated into clinical practice. In addition, γδT cells that have infiltrated into tumor tissues are found to be in a state of exhaustion or anergy, and there is upregulation of many immune checkpoints (ICs) on their surface, suggesting that γδT cells have a similar ability to respond to ICIs as traditional effector T cells. Studies have shown that targeting ICs can reverse the dysfunctional state of γδT cells in the tumor microenvironment (TME) and exert antitumor effects by improving γδT-cell proliferation and activation and enhancing cytotoxicity. Clarification of the functional state of γδT cells in the TME and the mechanisms underlying their interaction with ICs will solidify ICIs combined with γδT cells as a good treatment option.

T cell exhaustion presents one of the major hurdles to cancer immunotherapy. Among exhausted CD8 + tumor-infiltrating lymphocytes, the terminally exhausted subset contributes directly to tumor cell killing owing to its cytotoxic effector function. However, this subset does not respond to immune checkpoint blockades and is difficult to be reinvigorated with restored proliferative capacity. Here, we show that a half-life-extended interleukin-10–Fc fusion protein directly and potently enhanced expansion and effector function of terminally exhausted CD8 + tumor-infiltrating lymphocytes by promoting oxidative phosphorylation, a process that was independent of the progenitor exhausted T cells. Interleukin-10–Fc was a safe and highly efficient metabolic intervention that synergized with adoptive T cell transfer immunotherapy, leading to eradication of established solid tumors and durable cures in the majority of treated mice. These findings show that metabolic reprogramming by upregulating mitochondrial pyruvate carrier-dependent oxidative phosphorylation can revitalize terminally exhausted T cells and enhance the response to cancer immunotherapy. Tang and colleagues show that a half-life-extended IL-10–Fc fusion protein acts directly on terminally exhausted PD1 + TIM-3 + CD8 + T cells to enhance their proliferation and effector function by reprogramming the cellular metabolism to oxidative phosphorylation in a mitochondrial pyruvate carrier–dependent manner. Treatment of tumor-bearing mice with IL-10–Fc and adoptive T cell therapy led to eradication of their established solid tumors and durable cures.

The discovery and clinical implementation of immune-checkpoint inhibitors (ICIs) targeting CTLA4, PD-1 and PD-L1 has revolutionized the treatment of cancer, as recognized by the 2018 Nobel Prize for Medicine and Physiology. This groundbreaking new approach has improved the outcomes of patients with various forms of advanced-stage cancer; however, the majority of patients receiving these therapies, even in combination, do not derive clinical benefit. Further development of agents targeting additional immune checkpoints, co-stimulatory receptors and/or co-inhibitory receptors that control T cell function is therefore critical. In this Review, we discuss the translational potential and clinical development of agents targeting both co-stimulatory and co-inhibitory T cell receptors. Specifically, we describe their mechanisms of action, and provide an overview of ongoing clinical trials involving novel ICIs including those targeting LAG3, TIM3, TIGIT and BTLA as well as agonists of the co-stimulatory receptors GITR, OX40, 41BB and ICOS. We also discuss several additional approaches, such as harnessing T cell metabolism, in particular via adenosine signalling, inhibition of IDO1, and targeting changes in glucose and fatty acid metabolism. We conclude that further efforts are needed to optimize the timing of combination ICI approaches and, most importantly, to individualize immunotherapy based on both patient-specific and tumour-specific characteristics.Immune-checkpoint inhibitors have dramatically improved the outcomes in patients with advanced-stage cancers, although the majority of patients will not respond to these agents. Here, the authors describe the potential of targeting emerging immunomodulatory pathways, with a focus on alternative immune checkpoints and tumour metabolism as approaches that might enable further improvements in the outcomes of patients with cancer, either as monotherapies or in combination with existing agents.

Adjuvant chemotherapy has not improved disease-free survival among patients with resected esophageal or gastroesophageal junction cancer. In this trial, after neoadjuvant chemoradiotherapy and resection, patients with residual disease were randomly assigned to receive nivolumab or placebo. Nivolumab doubled the median disease-free survival from 11.0 to 22.4 months.

The immune system is the core defense against cancer development and progression. Failure of the immune system to recognize and eliminate malignant cells plays an important role in the pathogenesis of cancer. Tumor cells evade immune recognition, in part, due to the immunosuppressive features of the tumor microenvironment. Immunotherapy augments the host immune system to generate an antitumor effect. Immune checkpoints are pathways with inhibitory or stimulatory features that maintain self-tolerance and assist with immune response. The most well-described checkpoints are inhibitory in nature and include the cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1). Molecules that block these pathways to enhance the host immunologic activity against tumors have been developed and become standard of care in the treatment of many malignancies. Only a small percentage of patients have meaningful responses to these treatments, however. New pathways and molecules are being explored in an attempt to improve responses and application of immune checkpoint inhibition therapy. In this review, we aim to elucidate these novel immune inhibitory pathways, potential therapeutic molecules that are under development, and outline particular advantages and challenges with the use of each one of them.