PD-1 combination therapy with IL-2 modifies CD8⁺ T cell exhaustion program

Combination therapy with PD-1 blockade and IL-2 is highly effective during chronic lymphocytic choriomeningitis virus infection¹. Here we examine the underlying basis for this synergy. We show that PD-1 + IL-2 combination therapy, in contrast to PD-1 monotherapy, substantially changes the differentiation program of the PD-1⁺TCF1⁺ stem-like CD8⁺ T cells and results in the generation of transcriptionally and epigenetically distinct effector CD8⁺ T cells that resemble highly functional effector CD8⁺ T cells seen after an acute viral infection. The generation of these qualitatively superior CD8⁺ T cells that mediate viral control underlies the synergy between PD-1 and IL-2. Our results show that the PD-1⁺TCF1⁺ stem-like CD8⁺ T cells, also referred to as precursors of exhausted CD8⁺ T cells, are not fate-locked into the exhaustion program and their differentiation trajectory can be changed by IL-2 signals. These virus-specific effector CD8⁺ T cells emerging from the stem-like CD8⁺ T cells after combination therapy expressed increased levels of the high-affinity IL-2 trimeric (CD25-CD122-CD132) receptor. This was not seen after PD-1 blockade alone. Finally, we show that CD25 engagement with IL-2 has an important role in the observed synergy between IL-2 cytokine and PD-1 blockade. Either blocking CD25 with an antibody or using a mutated version of IL-2 that does not bind to CD25 but still binds to CD122 and CD132 almost completely abrogated the synergistic effects observed after PD-1 + IL-2 combination therapy. There is considerable interest in PD-1 + IL-2 combination therapy for patients with cancer^2,3, and our fundamental studies defining the underlying mechanisms of how IL-2 synergizes with PD-1 blockade should inform these human translational studies.