Immunotherapy: Open Access
Open Access

Impact of T-Cells on the Development of Antitumor Immunity

Leonardo Lynch^{* *}Correspondence: Leonardo Lynch, Department of Immunoreceptors and Signaling, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil, Email:

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Description

The main agents in antitumor immunity are T cells. Yet, T cells degenerate and develop their predicted efficiency for tumour immunity in the Tumour Microenvironment (TME), exhibiting reduced proliferative capacity, diminished effector activities, and overexpressed inhibitory receptors. T cell exhaustion is a symptom of T cell dysfunction in the TME, and exhausted T cells release a number of inhibitory receptors, such as CTLA-4, the lymphocyte activation gene 3 protein, T cell immunoglobulin domain and mucin domain protein 3, and programmed cell death protein 1 (PD-1) (LAG-3).

Immune checkpoint blockade therapy, which targets PD-1, PDL1, and/or CTLA-4, is designed to improve T cell function and has been successfully employed to boost antitumor T cell activity in a number of cancers. Yet, the overall success rates of the current checkpoint blockade therapy in a number of cancer types are just slightly better than 40%. The situation surrounding checkpoint blockade immunotherapy amply illustrates the existence of other alternative mechanisms other than weariness that could lead to cancer immunotherapy resistance in the TME.

Moreover, cellular senescence in Tumor-Infiltrating T cells (TILs) has recently been found to be a prominent T cell dysfunctional state produced by many malignant tumours. The development of mortality in effector T cells is significantly induced by tumour cells as well as tumor-associated regulatory T (Treg) cells. Senescent T cells have distinct phenotypes that set them apart from exhausted T cells, including expression of the enzyme senescence-associated -galactosidase (SA-gal), loss of the costimulatory molecules CD27 and CD28, upregulation of the cell cycle molecules P16, P53, and P21, secretion of proinflammatory and inhibitory cytokines, and strong suppressive activity. Senescent T cells, in addition to having decreased anticancer activity, can directly suppress DCs and effector T cells, cause adaptive Treg cells, and affect other immune cells within the TME. The recent data strongly suggest that senescent T cells play a significant role in amplifying and mediating immune suppression in the TME.

Hence, inhibiting effector T cell senescence may also be a key checkpoint and a useful strategy for tumour immunotherapy and antitumor immunity. When exposed to human Treg cells or tumour cells, responder T cells can senescence. Given the possible immunological differences between the mouse and human immune systems, it is critical for preclinical studies and translational research to establish whether the molecular pathways underlying T cell senescence also occur in the animal immune system. Responder T cells can age due to both mouse Treg cells and tumour cells.

Furthermore, it was found that the creation of T cell senescence, which is caused by DNA damage and MAPK signalling pathways, involves mouse Treg cells and tumour cells. In vivo studies in adoptive T cell transfer therapy for melanoma models shown that preventing DNA damage and/or MAPK P38 signalling can boost antitumor immunity and immunotherapy by preventing effector T cell senescence and dysfunction. Moreover, the use of an anti-PD-L1 antibody in conjunction with checkpoint blockade immunotherapy can enhance adoptive T cell transfer therapy for melanoma models by delaying T cell senescence by preventing DNA damage or P38 signalling. By simultaneously focusing on effector T cell senescence and exhaustion, immunotherapy for C cancer can be significantly improved.