The mechanism of action of PD-1 blockade in PD-L⁺tumors and models of potential functional effects of anti-PD-1 therapy on PD-1⁺T cells (CD4⁺/CD8⁺) in patients without PD-L expression (PD-L^–), according to the literature. (A) In PD-L⁺ tumors, the antigen-specific T-cell response is inhibited because PD-1 is engaged by PD-L1/2. PD-1 blockade with anti-PD-1 antibodies prevents PD-L1/PD-L2 from interacting with PD-1 and restores T-cell function (anti-PD-1 mAb acting as an antagonist). (B) In PD-L^– tumors with PD-1⁺CD4⁺ T-cell infiltrate, according to Chemnitz et al⁸⁰  and Bennett et al,¹²²  PD-1 ligation with PD-1 antibodies inhibits CD4⁺ T-cell proliferation and cytokine production under suboptimal CD3 and CD28 costimulation conditions (anti-PD-1 mAb acting as a PD-1 agonist), which are caused by inhibition of TCR downstream signaling mediated by SHP-2 associated with immunoreceptor tyrosine-based switch motif (ITSM) of PD-1. It is unknown whether this scenario is relevant for some hyperprogressive diseases after PD-1 blockade therapy. (C) The effect of anti-PD-1 antibodies on PD-1⁺CD8⁺ T cells in PD-L^– tumors is unknown. If the TCR signaling is strong with optimal CD28 costimulation and/or TCR engagement (in which case, PD-L^– is likely caused by mutations or lack of IFN-γ receptor on PD-L^– tumors, but not because of lack of IFN-γ release), PD-1 ligation with anti-PD-1 antibodies may have no significant effect on the high CD8⁺ T cell function.^2,122  Furthermore, if circulating activated T cells express PD-L1 and the PD-1−PD-L1 axis suppresses PD-1⁺ or PD-L1⁺ T-cell function, PD-1 blockade could enhance CD4⁺/CD8⁺ T-cell function, thereby manifesting clinical activity in these PD-L^– patients. (D) As another possibility for anti-PD-1 therapy in PD-L^– tumors, engagement of PD-1 on CD8⁺ T cells by PD-1 antibodies could inhibit TCR signaling (acting as a PD-1 agonist) similar to ligation with the natural ligand PD-L1, mediated by SHP-2 phosphatase activity and TCR internalization/degradation as a result of increased CBL-b ubiquitin ligase activity.¹²³  ITIM, immunoreceptor tyrosine-inhibitory motif.