ABSTRACT
Conventional CD4+ T (Tconv) lymphocytes play important roles in tumor immunity; however, their contribution to tumor elimination remains poorly understood. Here, we describe a subset of tumor-infiltrating Tconv cells characterized by the expression of CD39. In several mouse cancer models, we observed that CD39+ Tconv cells accumulated in tumors but were absent in lymphoid organs. Compared to tumor CD39− counterparts, CD39+ Tconv cells exhibited a cytotoxic and exhausted signature at the transcriptomic level, confirmed by high protein expression of inhibitory receptors and transcription factors related to the exhaustion. Additionally, CD39+ Tconv cells showed increased production of IFN, granzyme B, perforin and CD107a expression, but reduced production of TNF. Around 55% of OVA-specific Tconv from B16-OVA tumor-bearing mice, expressed CD39. In vivo CTLA-4 blockade induced the expansion of tumor CD39+ Tconv cells, which maintained their cytotoxic and exhausted features. In breast cancer patients, CD39+ Tconv cells were found in tumors and in metastatic lymph nodes but were less frequent in adjacent non-tumoral mammary tissue and not detected in non-metastatic lymph nodes and blood. Human tumor CD39+ Tconv cells constituted a heterogeneous cell population with features of exhaustion, high expression of inhibitory receptors and CD107a. We found that high CD4 and ENTPD1 (CD39) gene expression in human tumor tissues correlated with a higher overall survival rate in breast cancer patients. Our results identify CD39 as a biomarker of Tconv cells, with characteristics of both exhaustion and cytotoxic potential, and indicate CD39+ Tconv cells as players within the immune response against tumors.
Acknowledgments
We thank the staff of Cytometry Core, Animal and Cell culture of CIBICI-CONICET at the Facultad de Ciencias Químicas, UNC, and the Surgery Department of Hospital Rawson, Argentina. We also thank the staff of the Institut Curie Flow Cytometry facility and the Clinical Immunology Laboratory, Institut Curie, for the collection of human samples. We acknowledge the NIH Tetramer Core Facility for provision of tetramers.
Disclosure statement
E.P. is co-founder of Egle-Tx. E.P. and J.T are consultants for Egle-Tx. The other authors declare no conflicts of interest.
Author contributions
S.B. conducted experiments, analyzed and interpreted the data, and participated in manuscript writing. C. A., J. T-B., F.P.C. and C.R, participated in experiments with mice and revised the manuscript. V.B. participated in experiments with mice. M.C.R, C.S., participated in experiments with human samples. W.R., D.R., E.F. and J.T-B. participated in biostatistics and computational analysis. A.V-S, E.B. and A.del C. provided the biological material from cancer patients. A.G. and E.V.A.R. participated in data discussion, interpretation of results and manuscript revision. C.L.M. and E.P., designed and supervised the study, analyzed and interpreted the data and wrote the manuscript.
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
Sources of support
This work was supported by grants from PICT 2018–1787, SECYT 2018–2022, PIP-CONICET 2021–2023 to CL Montes. SNB, FPC, MCR, CR, and CA were supported by fellowships from CONICET. AG, EVAR, EF and CLM are members of the Scientific Career in CONICET. The TransImm team is supported by the SiRIC-Curie Program (grant INCa-DGOS-12554), the LabEx DCBIOL (ANR-10-IDEX-0001-02 PSL and ANR-11-LABX-0043, the Center of Clinical Investigation (CIC IGR-Curie 1428) and INCa- DGOSInserm_10.13039/501100006364 Institut National du Cancer 12554.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2246319
Abbreviations
BC | = | breast cancer |
PB | = | peripheral blood |
CTLs | = | cytotoxic T cells |
dLNs | = | draining lymph nodes |
iRs | = | inhibitory receptors |
M-dLNs | = | metastatic draining lymph nodes |
NM-dLNs | = | non-metastatic draining lymph nodes |
OS | = | overall survival |
Tconv | = | T conventional cells |
TFs | = | transcription factors |
T-I | = | tumor infiltrating |
TME | = | tumor microenvironment |
Treg | = | T regulatory cells |