T cell states, repertoire and function in classical Hodgkin lymphoma revealed through single-cell analyses.

The classical Hodgkin lymphoma (cHL) environment is comprised of a dense and complex immune cell infiltrate interspersed with rare malignant Hodgkin-Reed-Sternberg (HRS) cells. HRS cells are actively surveilled by endogenous T cells, but data linking phenotypic and functional T cell states with clonality at the single cell level in cHL is lacking. To address this knowledge gap, we performed paired single cell RNA and T cell receptor sequencing on 14 cHL and 5 reactive lymphoid tissue specimens. Conventional CD4+ T cells dominated the cHL landscape. However, recurrent clonal expansion within effector and exhausted CD8+ T cell and regulatory T cell clusters was uniquely observed in cHL specimens. Multi-plex flow cytometric analysis revealed that most lymphoma-resident T cells produced effector cytokines upon ex vivo restimulation, arguing against a profound dysfunctional T cell state in cHL. Our results raise new questions about the nature of T cells that mediate the anti-lymphoma response following PD-1 blockade therapy in cHL.