Fig. 1

Optimal human cancer-specific T-cell responses are determined by multiple factors: (1) T cells express specific TCRs with weak affinity to MHC loaded with self-antigenic peptides including tumor associated (TAA) or cancer germline antigens (CTA), while neoantigen or viral-onco antigen (foreign) would span the full range of affinities, especially high affinity TCRs. When strong and consistent stimulation of a T cell occurs, it becomes exhausted and starts to express inhibitory receptors like PD-1 and CTLA-4. There is also a class of inhibitory as well as co-stimulatory receptors expressed on CTL, independent of antigen stimulation and cell activation, such as CD94/NKG2A and CD103. (2) Together these factors determine the overall antigen sensitivity of T cells, and (3) the level of subsequent T-cell functions such as: killing ability, proliferation, energy consumption, etc. (4) The optimal function of T cells is determined by immune balance between all these factors, such that a T cell may preserve its ability to kill its target cells, to produce cytokines, and to migrate whilst preventing exhaustion and death. The reason why cancer cells may grow in an uncontrolled fashion is likely due to T cells in their environment becoming dysfunctional/exhaustion or ineffective as a result of too low or too high antigen sensitivity. Combination of approaches to maintain T-cell optimal function and specificity is the key to controlling cancer development in patients