Phased differentiation of gamma delta T and T CD8 tumor-infiltrating lymphocytes revealed by single-cell transcriptomics of human cancers

gamma delta 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 similar to 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 gamma delta T cell differentiation in cancer. While gamma delta T lymphocytes prominently encompass TCRV gamma 9 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 TCRV gamma non9 gamma delta 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.

Automated summary

This study provides the first detailed view of human gamma delta T cell differentiation in cancer, revealing a different differentiation pattern from healthy state. The majority of infiltrating T cells in solid tumors and lymphomas are TCRV gamma non9 gamma delta T cells, which shows quantitative correlation and remarkable alignment with T CD8 in terms of differentiation, exhaustion, gene expression profile, and response to immune checkpoint therapy, highlighting the importance of this cancer-wide association for developing cancer immunotherapies.