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. Pittet; Thorsten R. Mempel

doi:10.1016/j.cell.2021.07.015

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

Bloomberg School of Public Health

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	4512-4530.e22
Journal	Cell
Volume	184
Issue number	17
DOIs	https://doi.org/10.1016/j.cell.2021.07.015
State	Published - Aug 19 2021

Keywords

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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10.1016/j.cell.2021.07.015

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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., ... Mempel, T. R. (2021). CXCR6 positions cytotoxic T cells to receive critical survival signals in the tumor microenvironment. Cell, 184(17), 4512-4530.e22. https://doi.org/10.1016/j.cell.2021.07.015

Di Pilato, M, Kfuri-Rubens, R, Pruessmann, JN, Ozga, AJ, Messemaker, M, Cadilha, BL, Sivakumar, R, Cianciaruso, C, Warner, RD, Marangoni, F, Carrizosa, E, Lesch, S, Billingsley, J, Perez-Ramos, D, Zavala, F, Rheinbay, E, Luster, AD, Gerner, MY, Kobold, S, Pittet, MJ & Mempel, TR 2021, 'CXCR6 positions cytotoxic T cells to receive critical survival signals in the tumor microenvironment', Cell, vol. 184, no. 17, pp. 4512-4530.e22. https://doi.org/10.1016/j.cell.2021.07.015

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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.",

keywords = "CCR7 dendritic cells, CTL, CXCL16, CXCR6, IL-15, TCF-1, TCGA, multiphoton intravital microscopy, scRNA-seq, tumor microenvironment",

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year = "2021",

month = aug,

day = "19",

doi = "10.1016/j.cell.2021.07.015",

language = "English (US)",

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T1 - CXCR6 positions cytotoxic T cells to receive critical survival signals in the tumor microenvironment

AU - Di Pilato, Mauro

AU - Kfuri-Rubens, Raphael

AU - Pruessmann, Jasper N.

AU - Ozga, Aleksandra J.

AU - Messemaker, Marius

AU - Cadilha, Bruno L.

AU - Sivakumar, Ramya

AU - Cianciaruso, Chiara

AU - Warner, Ross D.

AU - Marangoni, Francesco

AU - Carrizosa, Esteban

AU - Lesch, Stefanie

AU - Billingsley, James

AU - Perez-Ramos, Daniel

AU - Zavala, Fidel

AU - Rheinbay, Esther

AU - Luster, Andrew D.

AU - Gerner, Michael Y.

AU - Kobold, Sebastian

AU - Pittet, Mikael J.

AU - Mempel, Thorsten R.

PY - 2021/8/19

Y1 - 2021/8/19

N2 - 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.

AB - 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.

KW - CCR7 dendritic cells

KW - CTL

KW - CXCL16

KW - CXCR6

KW - IL-15

KW - TCF-1

KW - TCGA

KW - multiphoton intravital microscopy

KW - scRNA-seq

KW - tumor microenvironment

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DO - 10.1016/j.cell.2021.07.015

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C2 - 34343496

AN - SCOPUS:85112780451

SN - 0092-8674

VL - 184

SP - 4512-4530.e22

JO - Cell

JF - Cell

IS - 17

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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