PDL1 shapes the classical Hodgkin lymphoma microenvironment without inducing T cell exhaustion

Abstract

Classical Hodgkin Lymphoma (CHL) is unusually sensitive to PD1 inhibition and PDL1 is highly expressed on CHL cells and in the tumor microenvironment. This could be interpreted as evidence of exhaustion, but paradoxically, PD1+ lymphocyte infiltration does not predict PD1 inhibitor response and no increase in cytotoxic markers is seen after PD1 therapy as might be expected with reversal of exhaustion. In contrast to PD1, elevated PDL1 does predict response to PD1 inhibitors and recent data associate both retained CHL MHC-II expression and increased T helper (TH) T-cell receptor diversity with response suggesting a connection to the TH compartment. We performed a phenotypic, spatial and functional assessment of T cell exhaustion in CHL and found lower PD1 expression and exhaustion marker co-expression in CHL as compared to reactive nodes and similar proliferative and cytokine production capacity. We found no correlation between PDL1 expression and exhaustion signatures. Instead, we identified a strong association between PDL1 expression and CHL MHC-II expression, TH recruitment, and enrichment of Th1 regulatory cells. These data suggest that a dominant effect of PDL1 expression in CHL may be T helper engagement and promotion of regulatory microenvironment rather than maintenance of exhaustion.