Circulating tumor-reactive KIR+CD8+ T cells suppress anti-tumor immunity in patients with melanoma

Benjamin Y Lu; Liliana E Lucca; Wesley Lewis; Jiping Wang; Catarina V Nogueira; Sebastian Heer; Violeta Rayon-Estrada; Pierre-Paul Axisa; Sarah M Reeves; Nicholas C Buitrago-Pocasangre; Giang H Pham; Mina L Kojima; Wei Wei; Lilach Aizenbud; Antonietta Bacchiocchi; Lin Zhang; Joseph J Walewski; Veronica Chiang; Kelly Olino; James Clune; Ruth Halaban; Yuval Kluger; Anthony J Coyle; Jan Kisielow; Franz-Josef Obermair; Harriet M Kluger; David A Hafler

doi:10.1038/s41590-024-02023-4

Circulating tumor-reactive KIR⁺CD8⁺ T cells suppress anti-tumor immunity in patients with melanoma

Nat Immunol. 2024 Nov 28. doi: 10.1038/s41590-024-02023-4. Online ahead of print.

Authors

Benjamin Y Lu^{1

2}, Liliana E Lucca^{3

4}, Wesley Lewis^{5

6}, Jiping Wang⁷, Catarina V Nogueira⁸, Sebastian Heer⁹, Violeta Rayon-Estrada⁸, Pierre-Paul Axisa^{3

4}, Sarah M Reeves¹⁰, Nicholas C Buitrago-Pocasangre³, Giang H Pham³, Mina L Kojima¹¹, Wei Wei¹², Lilach Aizenbud¹², Antonietta Bacchiocchi¹³, Lin Zhang¹², Joseph J Walewski³, Veronica Chiang¹⁴, Kelly Olino¹⁵, James Clune¹⁵, Ruth Halaban¹³, Yuval Kluger^{6

7}, Anthony J Coyle⁸, Jan Kisielow⁹, Franz-Josef Obermair⁹, Harriet M Kluger¹², David A Hafler^{16

17

18}

Affiliations

¹ Department of Medicine (Medical Oncology), Yale School of Medicine, New Haven, CT, USA. [email protected].
² Department of Neurology, Yale School of Medicine, New Haven, CT, USA. [email protected].
³ Department of Neurology, Yale School of Medicine, New Haven, CT, USA.
⁴ University of Toulouse, Inserm, CNRS, University Toulouse III-Paul Sabatier, Cancer Research Center of Toulouse, Toulouse, France.
⁵ Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA.
⁶ Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
⁷ Applied Mathematics Program, Yale University, New Haven, CT, USA.
⁸ Repertoire Immune Medicines, Cambridge, MA, USA.
⁹ Repertoire Immune Medicines, Schlieren, Switzerland.
¹⁰ Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
¹¹ Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
¹² Department of Medicine (Medical Oncology), Yale School of Medicine, New Haven, CT, USA.
¹³ Department of Dermatology, Yale School of Medicine, New Haven, CT, USA.
¹⁴ Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
¹⁵ Department of Surgery, Yale School of Medicine, New Haven, CT, USA.
¹⁶ Department of Neurology, Yale School of Medicine, New Haven, CT, USA. [email protected].
¹⁷ Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA. [email protected].
¹⁸ Broad Institute of MIT and Harvard University, Cambridge, MA, USA. [email protected].

PMID: 39609626
DOI: 10.1038/s41590-024-02023-4

Abstract

Effective anti-tumor immunity is driven by cytotoxic CD8⁺ T cells with specificity for tumor antigens. However, the factors that control successful tumor rejection are not well understood. Here we identify a subpopulation of CD8⁺ T cells that are tumor-antigen-specific and can be identified by KIR expression but paradoxically impair anti-tumor immunity in patients with melanoma. These tumor-antigen-specific KIR⁺CD8⁺ regulatory T cells target other tumor-antigen-specific CD8⁺ T cells, can be detected in both the tumor and the blood, have a conserved transcriptional program and are associated with a poor overall survival. These findings broaden our understanding of the transcriptional and functional heterogeneity of human CD8⁺ T cells and implicate KIR⁺CD8⁺ regulatory T cells as a cellular mediator of immune evasion in human cancer.

Abstract

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