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

Oncoimmunology. 2021 Sep 18;10(1):1939518. doi: 10.1080/2162402X.2021.1939518. eCollection 2021.


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.

Keywords: Gamma-delta lymphocyte; differentiation; scRNAseq.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes
  • Cell Differentiation
  • Humans
  • Lymphocytes, Tumor-Infiltrating
  • Mice
  • Neoplasms* / genetics
  • Receptors, Antigen, T-Cell, gamma-delta / genetics
  • T-Lymphocyte Subsets
  • Transcriptome*


  • Receptors, Antigen, T-Cell, gamma-delta

Grants and funding

This work was supported in part by institutional grants from the Institut National de la Santé et de la Recherche Médicale (INSERM), the Université Toulouse III-Paul Sabatier, the Centre National de la Recherche Scientifique (CNRS); Laboratoire d’Excellence Toulouse Cancer (TOUCAN-2) under grant contract ANR11-LABX, the Fondation ARC under grant contract PGA1-RF2019-0208691; Institut Universitaire du Cancer de Toulouse-Oncopole under contract CIEL; Institut Carnot Lymphome under cointract CALYM. This work was granted access to the HPC resources of CALMIP supercomputing center under allocation 2020-T19001. We are also grateful to the Genotoul bioinformatics platform (Bioinfo Genotoul, Toulouse Midi-Pyrenees) for providing computing resources;Fondation ARC pour la Recherche sur le Cancer [PGA1 RF20190208691];Institut Carnot CALYM [RAC21009BA];LabEx Toulouse Cancer [ANR11-LABX].