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; Fréderic Pont; Christel Devaud; Don-Marc Franchini; Virginie Féliu; Marie Tosolini; Carine Valle; Fréderic Lopez; Anne Quillet-Mary; Loic Ysebaert; Alejandra Martinez; Jean Pierre Delord; Maha Ayyoub; Camille Laurent; Jean-Jacques Fournie

doi:10.1080/2162402X.2021.1939518

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.

Authors

Juan-Pablo Cerapio^{1

2

3

4

5}, Marion Perrier^{1

2

3

4

5}, Camille-Charlotte Balança^{1

2

4}, Pauline Gravelle^{1

2

3

4

5

6

7}, Fréderic Pont^{1

2

3

4

5}, Christel Devaud^{1

2

4}, Don-Marc Franchini^{1

2

3

4

5

6

8}, Virginie Féliu^{1

2

4}, Marie Tosolini^{1

2

3

4

5}, Carine Valle^{1

2

3

4

5}, Fréderic Lopez^{1

2

3

4

5}, Anne Quillet-Mary^{1

2

3

4

5

6}, Loic Ysebaert^{1

2

3

4

5

6

7}, Alejandra Martinez^{1

2

4}, Jean Pierre Delord^{1

2

4

8}, Maha Ayyoub^{1

2

4}, Camille Laurent^{1

2

3

4

5

6

7}, Jean-Jacques Fournie^{1

2

3

4

5

6}

Affiliations

¹ Centre de Recherches en Cancérologie de Toulouse, INSERM UMR1037, Toulouse, France.
² Toulouse University, Toulouse, France.
³ CNRS UMR 5071, Toulouse, France.
⁴ Institut Universitaire du Cancer-Oncopole de Toulouse, Toulouse, France.
⁵ Laboratoire d'Excellence 'TOUCAN-2', Toulouse, France.
⁶ Institut Carnot Lymphome CALYM, France.
⁷ Centre Hospitalier Universitaire, Toulouse, France.
⁸ Institut Claudius Regaud, Toulouse, France.

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.

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*

Substances

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].