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

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 response to PD1 inhibitors 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 co-expression of an exhaustion marker and lower PD1 expression in CHL than in reactive nodes whereas the proliferative and cytokine production capacity were similar in CHL and the reactive nodes. 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 TH engagement and promotion of a regulatory microenvironment rather than maintenance of exhaustion.

Automated summary

Classical Hodgkin lymphoma (CHL) is highly sensitive to PD1 inhibition, and PDL1 is expressed in CHL cells and tumor microenvironment. However, the correlation between PD1 expression and response to PD1 inhibitors is not observed, and there is no increase in cytotoxic markers after PD1 therapy. In contrast, elevated PDL1 expression predicts response to PD1 inhibitors and is associated with CHL MHC-II expression, TH recruitment, and enrichment of TH1 regulatory cells.