Immune suppression in gliomas

Abstract

Introduction: The overall survival in patients with gliomas has not significantly increased in the modern era, despite advances such as immunotherapy. This is in part due to their notorious ability to suppress local and systemic immune responses, severely restricting treatment efficacy.

Methods: We have reviewed the preclinical and clinical evidence for immunosuppression seen throughout the disease process in gliomas. This review aims to discuss the various ways that brain tumors, and gliomas in particular, co-opt the body's immune system to evade detection and ensure tumor survival and proliferation.

Results: A multitude of mechanisms are discussed by which neoplastic cells evade detection and destruction by the immune system. These include tumor-induced T-cell and NK cell dysfunction, regulatory T-cell and myeloid-derived suppressor cell expansion, M2 phenotypic transformation in glioma-associated macrophages/microglia, upregulation of immunosuppressive glioma cell surface factors and cytokines, tumor microenvironment hypoxia, and iatrogenic sequelae of immunosuppressive treatments.

Conclusions: Gliomas create a profoundly immunosuppressive environment, both locally within the tumor and systemically. Future research should aim to address these immunosuppressive mechanisms in the effort to generate treatment options with meaningful survival benefits for this patient population.

Keywords: Gbm; Glioblastoma; Glioma; Immune suppression; Immunosuppression; Immunotherapy.

Fig. 1

Five domains of T-cell dysfunction. Clockwise from top left—Senescence: a Repetitive T-cell proliferation/activation and DNA damage events cause telomere shortening, decreasing the proliferative capacity of effector T-cells. b Thymic involution develops prematurely in patients with GBM, reducing T-cell output from the thymus. Tolerance: Gliomas induce T-cell apotosis via the FasL-Fas pathway, as well as generate proliferation of Tregs, which have suppressive effects on effector T-cells. Exhaustion: After repeated exposure under suboptimal conditions, T-cells end up expressing inhibitory immune checkpoints, with the major ones shown here. The degree of exhaustion is correlated with expression of specific checkpoints. Anergy: T-cell anergy can be caused by two broad mechanisms: insufficient co-stimulation leading to clonal anergy and impairment of T-cell activation, and continuous low level antigen exposure, leading to adaptive tolerance and reduced T-cell proliferation. Ignorance: T-cell ignorance is the result of fully functional T-cells that are prevented from antigen exposure by anatomical barriers or insufficient antigen expression levels, such as is the case with the blood brain barrier and T-cell sequestration. T Eff effector T-cell, ROS reactive oxygen species, RTE recent thymic emigrants TRECs T-cell receptor excision circles, T reg regulatory T-cell, MHC major histocompatibility complex, TCR T-cell receptor. Created with BioRender.com

Fig. 2

Summary of glioma-immune interactions. Gliomas secrete or express a variety of factors that attract or induce immunosuppressive cell types, or have direct inhibitory effects on immune effector cells. T Eff effector T cell, ROS reactive oxygen species, NO nitric oxide, GAM glioma-associated microglia/macrophage, MDSC myeloid-derived suppressor cell, T reg regulatory T cell, MHC major histocompatibility complex, APC antigen presenting cell. Created with BioRender.com