T cell dysfunction and therapeutic intervention in cancer

Abstract

Recent advances in immunotherapy have affirmed the curative potential of T cell-based approaches for treating relapsed and refractory cancers. However, the therapeutic efficacy is limited in part owing to the ability of cancers to evade immunosurveillance and adapt to immunological pressure. In this Review, we provide a brief overview of cancer-mediated immunosuppressive mechanisms with a specific focus on the repression of the surveillance and effector function of T cells. We discuss CD8⁺ T cell exhaustion and functional heterogeneity and describe strategies for targeting the molecular checkpoints that restrict T cell differentiation and effector function to bolster immunotherapeutic effects. We also delineate the emerging contributions of the tumor microenvironment to T cell metabolism and conclude by highlighting discovery-based approaches for developing future cellular therapies. Continued exploration of T cell biology and engineering hold great promise for advancing therapeutic interventions for cancer.

Figure 1.. Cancer immune evasion

Several strategies exist for cancer to evade the immune system. These impediments includes T cell exhaustion, upregulation of inhibitory receptors, cell mediated repression (such as by regulatory T (Treg) cells), secretion of suppressive cytokines, nutrient depletion, metabolic dysfunction, immune escape and an immunosuppressive tumor microenvironment.

Figure 2.. T cell differentiation and exhaustion

A) In settings of acute antigen exposure, T cells differentiate into terminal effectors or a long-lived memory population. If exposed to chronic antigen, T cells can acquire functional features of terminal exhaustion. B) The tumor microenvironment suppresses T cell anti-tumor function and maintenance of the ICB-responsive Tpex population. This suppression is in part a result of anatomical location of these cells within the lymph nodes. The TCF-1⁺ Tpex population can self-renew and mount a proliferative burst in response to ICB, whereas the Tex cell population within the tumor lacks the ability to respond to ICB.

Figure 3.. Rational design for future T cell therapies

CAR T cells are manufactured using a heterogeneous pool of T cells. After infusion into the patient, longitudinal analysis of CAR T cells will allow for identification of gene mutations and vector integration site disruptions that are associated with proliferative potential and a durable anti-tumor response. Survival associated variants for engineering (SAVE analysis) is permissive for patient-identified regulators of T cell durability to inform the engineering of next generation T cell-based cellular therapies.