Phased differentiation of γδ T and T CD8 tumor-infiltrating lymphocytes revealed by single-cell transcriptomics of human cancers
Juan‐Pablo Cerapio, Marion Perrier, Camille-Charlotte Balança, Pauline Gravelle, Frédéric Pont, Christel Devaud, Don‐Marc Franchini, Virginie Féliu, Marie Tosolini, Carine Valle, Frédéric Lopez, Anne Quillet‐Mary, Loïc Ysebaert, Alejandra Martínez, Jean Pierre Delord, Maha Ayyoub, Camille Laurent, Jean‐Jacques Fournié
Abstract
γδ T lymphocytes diverge from conventional T CD8 lymphocytes for ontogeny, homing, and antigen specificity, but whether their differentiation in tumors also deviates was unknown. Using innovative analyses of our original and ~150 published single-cell RNA sequencing datasets validated by phenotyping of human tumors and murine models, here we present the first high-resolution view of human γδ T cell differentiation in cancer. While γδ T lymphocytes prominently encompass TCRVγ9 cells more differentiated than T CD8 in healthy donor's blood, a different scenario is unveiled in tumors. Solid tumors and lymphomas are infiltrated by a majority of TCRVγnon9 γδ T cells which are quantitatively correlated and remarkably aligned with T CD8 for differentiation, exhaustion, gene expression profile, and response to immune checkpoint therapy. This cancer-wide association is critical for developing cancer immunotherapies.