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Cited by 488Chemokine receptors and signalingCancer Immunotherapy and BiomarkersT-cell and B-cell Immunology

CXCR6 positions cytotoxic T cells to receive critical survival signals in the tumor microenvironment

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Di Pilato, Mauro, Kfuri-Rubens, Raphael, Pruessmann, Jasper N., Ozga, Aleksandra J., Messemaker, Marius, Cadilha, Bruno L., Sivakumar, Ramya, Cianciaruso, Chiara +13 more·2021·Cell
DOI 10.1016/j.cell.2021.07.015PMC PMC8719451
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Abstract

Cytotoxic T lymphocyte (CTL) responses against tumors are maintained by stem-like memory cells that self-renew but also give rise to effector-like cells. The latter gradually lose their anti-tumor activity and acquire an epigenetically fixed, hypofunctional state, leading to tumor tolerance. Here, we show that the conversion of stem-like into effector-like CTLs involves a major chemotactic reprogramming that includes the upregulation of chemokine receptor CXCR6. This receptor positions effector-like CTLs in a discrete perivascular niche of the tumor stroma that is densely occupied by CCR7+ dendritic cells (DCs) expressing the CXCR6 ligand CXCL16. CCR7+ DCs also express and trans-present the survival cytokine interleukin-15 (IL-15). CXCR6 expression and IL-15 trans-presentation are critical for the survival and local expansion of effector-like CTLs in the tumor microenvironment to maximize their anti-tumor activity before progressing to irreversible dysfunction. These observations reveal a cellular and molecular checkpoint that determines the magnitude and outcome of anti-tumor immune responses.

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Authors
Di Pilato, M., Kfuri-Rubens, R., Pruessmann, J. N., Ozga, A. J., Messemaker, M., Cadilha, B. L., Sivakumar, R., Cianciaruso, C., Warner, R. D., Marangoni, F., Carrizosa, E., Lesch, S., Billingsley, J., Perez-Ramos, D., Zavala, F., Rheinbay, E., Luster, A. D., Gerner, M. Y., Kobold, S., Pittet, M. J., & Mempel, T. R.
Affiliations
  • Harvard University (US)
  • Massachusetts General Hospital (US)
  • LMU Klinikum (DE)
  • University of Washington (US)
  • Johns Hopkins University (US)
Corresponding author
Mempel, Thorsten R.
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2021-08
Volume
184
Issue
17
Pages
4512-4530.e22
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2021.07.015
PMC
PMC8719451
OpenAlex
W3189614948
Cited by
488
References
17
Citations by year
2026: 101 · 2025: 118 · 2024: 107 · 2023: 88 · 2022: 60 · 2021: 13 · 2013: 1
FWCI
24.41
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Archive ouverte UNIGE (University of Geneva) (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • IRIS (submittedVersion)
  • SERVAL (Université de Lausanne) (submittedVersion)
  • Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
Funders
  • Melanoma Research Foundation
  • Elitenetzwerk Bayern
  • EMBO (ALTF534-2015)
  • Melanoma Research Alliance (827872)
  • Swiss National Science Foundation (P3BEP3_165406)
  • American Association for Cancer Research (PCT/EP2016/074644, 18-40-01-OZGA)
  • Marie Curie
  • European Commission (955575, 750973, 756017)
  • Fondation ISREC
  • Liaoning Medical University
  • Deutsche Forschungsgemeinschaft (PR 1652/1-1, PR 1652/2-1)
  • Engineering Research Centers
  • Bundesministerium für Bildung und Forschung
  • NIH (R01 CA206890, P01-CA240239, R01 AI123349, R21AI142667, R01 AI134713, R01 CA204028, R01 AI084880, R01 CA218579)
Topics
  • Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
CXCR6, cytotoxic T lymphocytes, tumor microenvironment, IL-15, dendritic cells, T cell survival, antitumor immunity, immune checkpoint
MeSH terms
Chemokine CXCL16, Receptors, CXCR6, Animals, Cell Communication, Cell Movement, Cell Survival, Dendritic Cells, Ligands, Lymph Nodes, Melanoma, Mice, Inbred C57BL, T-Lymphocytes, Cytotoxic, Interleukin-12, Interleukin-15, Cell Proliferation, Mice, Tumor Microenvironment, B7-H1 Antigen

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