Role of T Lymphocytes in Glioma Immune Microenvironment: Two Sides of a Coin

Simple Summary Gliomas are diverse types of tumors originating from glial cells. Among these tumors, glioblastoma multiforme (GBM) is the most aggressive form and has a poor prognosis and high mortality rate, with treatment success largely influenced by patient age, tumor location, and genetic mutations. Glioma cells can reprogram their tumor microenvironment (TME) to support tumor proliferation and survival, interacting with other cells through cytokines and growth factors. The TME of gliomas is highly heterogeneous, complex, and often immunosuppressive, interfering with treatment strategies. Current therapeutic strategies focus on modulating immune cell activities and enhancing anti-tumor responses. T-cell-based immunotherapies are being explored to target glioma cells. These include chimeric antigen receptor (CAR) T-cell therapy and T-cell receptor (TCR) therapy, which involve engineering T cells to recognize tumor antigens. However, these therapies face multiple challenges including tumor heterogeneity, immunosuppression by T cell exhaustion, and altered antigen presentation, etc. Future research should focus on boosting T cell functions, targeting immune checkpoints, and developing more effective delivery methods to improve treatment outcomes for glioma patients.Abstract Glioma is known for its immunosuppressive microenvironment, which makes it challenging to target through immunotherapies. Immune cells like macrophages, microglia, myeloid-derived suppressor cells, and T lymphocytes are known to infiltrate the glioma tumor microenvironment and regulate immune response distinctively. Among the variety of immune cells, T lymphocytes have highly complex and multifaceted roles in the glioma immune landscape. T lymphocytes, which include CD4+ helper and CD8+ cytotoxic T cells, are known for their pivotal roles in anti-tumor responses. However, these cells may behave differently in the highly dynamic glioma microenvironment, for example, via an immune invasion mechanism enforced by tumor cells. Therefore, T lymphocytes play dual roles in glioma immunity, firstly by their anti-tumor responses, and secondly by exploiting gliomas to promote immune invasion. As an immunosuppression strategy, glioma induces T-cell exhaustion and suppression of effector T cells by regulatory T cells (Tregs) or by altering their signaling pathways. Further, the expression of immune checkpoint inhibitors on the glioma cell surface leads to T cell anergy and dysfunction. Overall, this dynamic interplay between T lymphocytes and glioma is crucial for designing more effective immunotherapies. The current review provides detailed knowledge on the roles of T lymphocytes in the glioma immune microenvironment and helps to explore novel therapeutic approaches to reinvigorate T lymphocytes.