Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Cell, 2021-08, Vol.184 (17), p.4512-4530.e22

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2021

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •CXCR6 is critical for sustained tumor control mediatedby CD8+ cytotoxic T cells (CTLs)•CXCR6 optimizes CTL interactions with the CCR7+ DC3 state of conventional DCs•DC3s trans-present IL-15 to TCF-1neg effector-like CTLs to sustain their survival in the TME•DC3s densely cluster in T cell-rich perivascular niches of the tumor stroma Intravital imaging reveals how the chemokine receptor CXCR6 positions CD8+ cytotoxic T cells in a distinct perivascular niche of the tumor stroma that is populated by CCR7+ dendritic cells expressing the CXCR6-ligand CXCL16 and trans-presenting the cytokine IL-15. This molecular checkpoint allows for the survival and expansion of CD8+ T cells to enable a potent anti-tumor immune response.