Fig. 2

Identified T-cell subset pathways modulating the action of anti-PD-1 on the tumor. Anti-PD-1 antibodies are suggested to engage distinct transcription factor T cell factor 1 (TCF-1) expressing precursor CD8⁺ T cell subsets, thereby inducing either their self-regeneration or their further differentiation into terminal effector CD8⁺ T cells. Enhanced tumor infiltration by cytotoxic T cells and CD8⁺ memory T cells both stand as correlates of an effective re-invigoration of the anti-tumoral immune response under PD-1 blockade. Anti-PD-1 can also directly engage an immune suppressive Foxp3⁻ CD4⁺ T cell subset expressing high levels of PD-1 and displaying a T follicular-helper profile (4PD1Hi) cells, inducing their downregulation in the tumor microenvironment and in the periphery. Anti-PD-1 may also contribute to anti-tumoral immunity by infringing the inhibition of effector T cells by PD-1⁺ Tregs in the TME mediated by direct cell contact (trans mechanism). PD-1 blockade also induces potentially opposite cis-effects on PD-1⁺ Tregs, leading either to their downregulation (reduced immune suppressive function and downregulating Foxp-3 expression) or to their expansion (through the reversal of a functional state of exhaustion). Anti-PD-1 antibodies may induce the expansion of immune suppressive CD8 + T cell subsets, including that of a CD38⁺ PD-1⁺ CD8⁺ T cell subset suggested to result from suboptimal priming, which will have an adverse influence on the anti-cancer immune response