Boosting gamma delta T cell-mediated antibody-dependent cellular cytotoxicity by PD-1 blockade in follicular lymphoma

Follicular lymphoma (FL) is a common non Hodgkin's lymphoma subtype in which immune escape mechanisms are implicated in resistance to chemo-immunotherapy. Although molecular studies point to qualitative and quantitative deregulation of immune checkpoints, in depth cellular analysis of FL immune escape is lacking. Here, by functional assays and in silico analyses we show that a subset of FL patients displays a `high' immune escape phenotype. These FL cases are characterized by abundant infiltration of PD1(+) CD16(+) TCRV gamma 9V delta 2 gamma delta T lymphocytes. In a 3D co-culture assay (MALC), gamma delta T cells mediate both direct and indirect (ADCC in the presence of anti-CD20 mAbs) cytolytic activity against FL cell aggregates. Importantly, PD-1, which is expressed by most FL-infiltrating gamma delta T lymphocytes with ADCC capacity, impairs these functions. In conclusion, we identify a PD1-regulated gamma delta T cell cytolytic immune component in FL. Our data provide a treatment rational by PD-1 blockade aimed at boosting gamma delta T cell anti-tumor functions in FL.