PD-1/PD-L1 co-inhibition shapes anticancer T cell immunodominance: facing the consequences of an immunological ménage à trois.

PD-1- and PD-L1-blocking monoclonal antibodies have shown significant promise in clinical settings and rekindled the hope for successful cancer immunotherapy. We recently demonstrated that interfering with PD-1/PD-L1 signaling selectively augments CD8+ T cell (TCD8 ) responses to subdominant determinants (SDDs) of a model tumor antigen. This was likely due to decreased lysis of SDD-specific TCD8 by neighboring immunodominant clones co-engaging the same antigen-presenting cells (APCs). We therefore proposed that PD-1-based checkpoint inhibitors widen the range of tumor determinants that can be effectively targeted by TCD8 . Subsequently and using different tumor models, Chen et al. reported, in Proceedings of the National Academy of Sciences of the United States of America, that PD-L1 protects APCs from the lytic function of immunodominant TCD8 and that PD-L1 blockade narrows, rather than broadens, the overall anticancer T cell response. Here, we briefly compare and contrast the experimental systems employed by the two groups, which may account, at least partially, for the opposing conclusions drawn. We argue that the pathway(s) of tumor antigen presentation, direct presentation versus cross-presentation, and the intensity of PD-1 expression by immunodominant and subdominant TCD8 must be taken into consideration in rational design of anti-PD-1/PD-L1-adjuvanted tumor vaccines and therapies.