Figure 2.

Model of the characteristics and differentiation of CD8⁺ T cell states in cancer. The transcription factors TCF1 and LEF1, as well as the adhesion and lymphocyte homing molecules CD62L, are highly expressed in naïve T cells. Downstream, the population of stem-like CD8⁺ T (T_SL) cells with strong polyfunctionality and self-renewal ability is defined by TCF1. These cells have a strong proliferation capacity, are primarily quiescent in vivo, and are able to support the CD8⁺ T cell response. By suppressing the expression of effector-associated genes like Id2, Blimp-1, Tbet and Tbx21 and stimulating memory-associated genes like Eomes, Myb, Bcl-6, TCF1 facilitates the generation, maintenance, and functionality of these cells. Phenotypically, T_SL cells display CD28 and ICOS costimulatory markers, low or moderate amounts of PD-1, SLAMF6, and CXCR5. T_SL cells expand upon ICB and both maintain the T_SL reservoir and differentiate into further subpopulations. Differentiation of T_SL give rise to downstream transitory effector CD8⁺ T cells (T_TE) that express high PD-1 receptor, proliferate rapidly in steady state down regulating TCF1 expression, and upregulate T-BET. T-BET inhibits TOX-mediated development of late dysfunctional T cells (T_LD) phenotype in T_TE cells. Transitory cells exhibit the expression of CX3 chemokine receptor 1 (CX3CR1) and PD-1. T_TE proliferate to help target and eliminate tumor cells. After chronic antigen stimulation, these T_TE cells develop into T_LD cells which are characterized by high expression of checkpoint receptors (PD-1, TIM3, LAG3, CTLA-4, TIGIT, and CD101), poor polyfunctionality, low proliferation capacity, but retain some cytotoxic potential.