Intratumoral CD8+ T cells with a tissue-resident memory phenotype mediate local immunity and immune checkpoint responses in breast cancer

Balaji Virassamy; Franco Caramia; Peter Savas; Sneha Sant; Jianan Wang; Susan N Christo; Ann Byrne; Kylie Clarke; Emmaline Brown; Zhi Ling Teo; Bianca von Scheidt; David Freestone; Luke C Gandolfo; Karsten Weber; Julia Teply-Szymanski; Ran Li; Stephen J Luen; Carsten Denkert; Sibylle Loibl; Olivia Lucas; Charles Swanton; Terence P Speed; Phillip K Darcy; Paul J Neeson; Laura K Mackay; Sherene Loi

doi:10.1016/j.ccell.2023.01.004

Intratumoral CD8⁺ T cells with a tissue-resident memory phenotype mediate local immunity and immune checkpoint responses in breast cancer

Cancer Cell. 2023 Mar 13;41(3):585-601.e8. doi: 10.1016/j.ccell.2023.01.004. Epub 2023 Feb 23.

Authors

Balaji Virassamy¹, Franco Caramia¹, Peter Savas², Sneha Sant², Jianan Wang³, Susan N Christo⁴, Ann Byrne¹, Kylie Clarke¹, Emmaline Brown¹, Zhi Ling Teo², Bianca von Scheidt¹, David Freestone⁵, Luke C Gandolfo⁶, Karsten Weber⁷, Julia Teply-Szymanski⁸, Ran Li¹, Stephen J Luen², Carsten Denkert⁸, Sibylle Loibl⁷, Olivia Lucas⁹, Charles Swanton¹⁰, Terence P Speed¹¹, Phillip K Darcy¹², Paul J Neeson¹³, Laura K Mackay¹⁴, Sherene Loi¹⁵

Affiliations

¹ Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
² Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; The Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Melbourne, VIC, Australia.
³ Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia.
⁴ Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia; Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
⁵ Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
⁶ Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
⁷ German Breast Cancer Group, GBG-Forschungs GmbH, Neu-Isenburg, Germany.
⁸ German Breast Cancer Group, GBG-Forschungs GmbH, Neu-Isenburg, Germany; Department of Pathology, University Marburg-Giessen, Campus Marburg, Germany.
⁹ Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK; Computational Cancer Genomics Research Group, University College London Cancer Institute, London, UK.
¹⁰ Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK.
¹¹ Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia; School of Mathematics and Statistics, University of Melbourne, Melbourne, VIC, Australia.
¹² Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; The Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Melbourne, VIC, Australia. Electronic address: phil.darcy@petermac.org.
¹³ Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; The Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Melbourne, VIC, Australia. Electronic address: paul.neeson@petermac.org.
¹⁴ Department of Medical Biology, The University of Melbourne, Melbourne, VIC, Australia; Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia. Electronic address: lkmackay@unimelb.edu.au.
¹⁵ Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; The Sir Peter MacCallum Department of Medical Oncology, University of Melbourne, Melbourne, VIC, Australia. Electronic address: sherene.loi@petermac.org.

PMID: 36827978
DOI: 10.1016/j.ccell.2023.01.004

Abstract

CD8⁺ tumor-infiltrating lymphocytes with a tissue-resident memory T (T_RM) cell phenotype are associated with favorable prognosis in patients with triple-negative breast cancer (TNBC). However, the relative contribution of CD8⁺ T_RM cells to anti-tumor immunity and immune checkpoint blockade efficacy in breast cancer remains unknown. Here, we show that intratumoral CD8⁺ T cells in murine mammary tumors transcriptionally resemble those from TNBC patients. Phenotypic and transcriptional studies established two intratumoral sub-populations: one more enriched in markers of terminal exhaustion (T_EX-like) and the other with a bona fide resident phenotype (T_RM-like). Treatment with anti-PD-1 and anti-CTLA-4 therapy resulted in expansion of these intratumoral populations, with the T_RM-like subset displaying significantly enhanced cytotoxic capacity. T_RM-like CD8⁺ T cells could also provide local immune protection against tumor rechallenge and a T_RM gene signature extracted from tumor-free tissue was significantly associated with improved clinical outcomes in TNBC patients treated with checkpoint inhibitors.

Keywords: CTLA-4; PD-1; cancer immune surveillance; cancer immunotherapy; immune checkpoint blockade; intratumoral CD8(+) T cells; tissue-resident memory cells; triple-negative breast cancer; tumor immunity; tumor infiltrating lymphocytes.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CD8-Positive T-Lymphocytes*
Humans
Immunologic Memory
Lymphocytes, Tumor-Infiltrating
Mice
Phenotype
Prognosis
Triple Negative Breast Neoplasms* / drug therapy
Triple Negative Breast Neoplasms* / genetics

Abstract

Publication types

MeSH terms

Grants and funding