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

Mauro Di Pilato, Raphael Kfuri-Rubens, Jasper N. Pruessmann, Aleksandra J. Ozga, Marius Messemaker, Bruno L. Cadilha, Ramya Sivakumar, Chiara Cianciaruso, Ross D. Warner, Francesco Marangoni, Esteban Carrizosa, Stefanie Lesch, James Billingsley, Daniel Perez-Ramos, Fidel Zavala, Esther Rheinbay, Andrew D. Luster, Michael Y. Gerner, Sebastian Kobold, Mikael J. PittetThorsten R. Mempel

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)4512-4530.e22
Issue number17
StatePublished - Aug 19 2021


  • CCR7 dendritic cells
  • CTL
  • CXCL16
  • CXCR6
  • IL-15
  • TCF-1
  • TCGA
  • multiphoton intravital microscopy
  • scRNA-seq
  • tumor microenvironment

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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