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. 2025 Mar 3;222(2):e20240776.
doi: 10.1084/jem.20240776. Epub 2025 Jan 22.

The XCL1-XCR1 axis supports intestinal tissue residency and antitumor immunity

Amir Ferry  1 , Kianoosh M Mempel  1 , Alexander Monell  1 , Miguel Reina-Campos  1   2 , Nicole E Scharping  1 , Maximilian Heeg  1 , Kennidy K Takehara  1 , Shiruyeh Schokrpur  3 , Ning Kuo  3 , Robert Saddawi-Konefka  3 , J Silvio Gutkind  3 , Ananda W Goldrath  1   4
Affiliations

The XCL1-XCR1 axis supports intestinal tissue residency and antitumor immunity

Amir Ferry et al. J Exp Med. .

Abstract

Tissue-resident memory T cells (TRM) provide frontline protection against pathogens and emerging malignancies. Tumor-infiltrating lymphocytes (TIL) with TRM features are associated with improved clinical outcomes. However, the cellular interactions that program TRM differentiation and function are not well understood. Using murine genetic models and targeted spatial transcriptomics, we found that the CD8+ T cell-derived chemokine XCL1 is critical for TRM formation and conventional DC1 (cDC1) supported the positioning of intestinal CD8+ T cells during acute viral infection. In tumors, enforced Xcl1 expression by antigen-specific CD8+ T cells promoted intratumoral cDC1 accumulation and T cell persistence, leading to improved overall survival. Notably, analysis of human TIL and TRM revealed conserved expression of XCL1 and XCL2. Thus, we have shown that the XCL1-XCR1 axis plays a non-cell autonomous role in guiding intestinal CD8+ TRM spatial differentiation and tumor control.

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Conflict of interest statement

Disclosures: A. Ferry reported other from TCura Bioscience outside the submitted work; in addition, A. Ferry had a patent application pending. M. Reina-Campos and A.W. Goldrath are co-founders and scientific advisory board members of TCura Bioscience, Inc. J.S. Gutkind reported non-financial support from Kadima Pharmaceuticals, Inc., and personal fees from Pangea Therapeutics, BTB Therapeutics, Radionetics, I90 LLC, and Domain Pharmaceuticals during the conduct of the study. A.W. Goldrath reported personal fees from ArsenalBio during the conduct of the study and other from ArsenalBio outside the submitted work; in addition, A.W. Goldrath had a patent pending. No other disclosures were reported.

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