51. Intratumoral CD8 + T cells with a tissue-resident memory phenotype mediate local immunity and immune checkpoint responses in breast cancer.
- Author
-
Virassamy B, Caramia F, Savas P, Sant S, Wang J, Christo SN, Byrne A, Clarke K, Brown E, Teo ZL, von Scheidt B, Freestone D, Gandolfo LC, Weber K, Teply-Szymanski J, Li R, Luen SJ, Denkert C, Loibl S, Lucas O, Swanton C, Speed TP, Darcy PK, Neeson PJ, Mackay LK, and Loi S
- Subjects
- Humans, Animals, Mice, Immunologic Memory, Phenotype, Prognosis, Lymphocytes, Tumor-Infiltrating, CD8-Positive T-Lymphocytes, Triple Negative Breast Neoplasms drug therapy, Triple Negative Breast Neoplasms genetics
- Abstract
CD8
+ tumor-infiltrating lymphocytes with a tissue-resident memory T (TRM ) cell phenotype are associated with favorable prognosis in patients with triple-negative breast cancer (TNBC). However, the relative contribution of CD8+ TRM 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 (TEX -like) and the other with a bona fide resident phenotype (TRM -like). Treatment with anti-PD-1 and anti-CTLA-4 therapy resulted in expansion of these intratumoral populations, with the TRM -like subset displaying significantly enhanced cytotoxic capacity. TRM -like CD8+ T cells could also provide local immune protection against tumor rechallenge and a TRM gene signature extracted from tumor-free tissue was significantly associated with improved clinical outcomes in TNBC patients treated with checkpoint inhibitors., Competing Interests: Declaration of interests P.S. receives research funding from Roche-Genentech. S.Loi receives research funding to her institution from Novartis, Bristol-Meyers Squibb, Merck, Puma Biotechnology, Eli Lilly, Nektar Therapeutics, Astra Zeneca, Roche-Genentech, and Seattle Genetics. S.Loi has acted as consultant (not compensated) to Seattle Genetics, Novartis, Bristol-Meyers Squibb, Merck, AstraZeneca, Eli Lilly, Pfizer, and Roche-Genentech. S.Loi has acted as consultant (paid to her institution) to Aduro Biotech, Novartis, GlaxoSmithKline, Roche-Genentech, Astra Zeneca, Silverback Therapeutics, G1 Therapeutics, PUMA Biotechnologies, Pfizer, Gilead Therapeutics, Seattle Genetics, Daiichi-Sankyo, Amunix, Tallac Therapeutics, Eli Lilly, and Bristol-Meyers. S. Loi has filed a provisional patent application in Australia based on methods for patient stratification described in this manuscript. Squibb. P.K.D. receives research funding from Myeloid Therapeutics, Prescient Therapeutics, and Bristol-Myers Squibb. S.Loibl reports grants and other from Abbvie; other from Amgen; grants and other from AstraZeneca; other from BMS; grants and other from Celgene; grants, non-financial support, and other from Daiichi-Sankyo; other from Eirgenix; other from Eisai Europe Ltd; other from GSK; grants, non-financial support, and other from Immunomedics/Gilead; other from Lilly; other from Merck; grants from Molecular Health; grants, non-financial support, and other from Novartis; grants, non-financial support, and other from Pfizer; other from Pierre Fabre; other from Relay Therapeutics; grants, non-financial support, and other from Roche; other from Sanofi; non-financial support and other from Seagen, outside the submitted work. In addition, S.Loibl has a patent EP14153692.0 pending, a patent EP21152186.9 pending, a patent P15702464.7 issued, a patent EP19808852.8 pending, and a patent Digital Ki67 Evaluator with royalties paid. C.S. acknowledges grant support from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Pfizer, Roche-Ventana, Invitae (previously Archer Dx Inc - collaboration in minimal residual disease sequencing technologies), and Ono Pharmaceutical. He is an AstraZeneca Advisory Board member and Chief Investigator for the AZ MeRmaiD 1 and 2 clinical trials and is Co-Chief Investigator of the NHS Galleri trial funded by GRAIL and a paid member of GRAIL’s Scientific Advisory Board. He receives consultant fees from Achilles Therapeutics (also SAB member), Bicycle Therapeutics (also a SAB member), Genentech, Medicxi, Roche Innovation Center – Shanghai, Metabomed (until July 2022), and the Sarah Canon Research Institute. C.S has received honoraria from Amgen, AstraZeneca, Pfizer, Novartis, GlaxoSmithKline, MSD, Bristol-Myers Squibb, Illumina, and Roche-Ventana. C.S. had stock options in Apogen Biotechnologies and GRAIL until June 2021, and currently has stock options in Epic Bioscience, Bicycle Therapeutics, and has stock options and is co-founder of Achilles Therapeutics. C.S. holds patents relating to assay technology to detect tumor recurrence (PCT/GB2017/053289); to targeting neoantigens (PCT/EP2016/059401), identifying patent response to immune checkpoint blockade (PCT/EP2016/071471), determining HLA LOH (PCT/GB2018/052004), predicting survival rates of patients with cancer (PCT/GB2020/050221), identifying patients who respond to cancer treatment (PCT/GB2018/051912), US patent relating to detecting tumor mutations (PCT/US2017/28013), methods for lung cancer detection (US20190106751A1) and both a European and US patent related to identifying insertion/deletion mutation targets (PCT/GB2018/051892). C.D. reports grants from European Commission H2020, grants from German Cancer Aid Translational Oncology, grants from German Breast Group, during the conduct of the study; personal fees from Novartis, Roche, MSD Oncology, Daiichi Sankyo, AstraZeneca, Merck, Molecular Health, grants from Myriad and Roche to the institution, grants from GBG foundation to the institution, other from Sividon diagnostics, outside the submitted work; In addition, Dr. Denkert has a patent on VMscope digital pathology software with royalties paid, a patent WO2020109570A1 - cancer immunotherapy pending, and a patent WO2015114146A1 and WO2010076322A1- therapy response issued.A provisional patent application has been filed in Australia based on methods for patient stratification disclosed in this manuscript., (Copyright © 2023 Elsevier Inc. All rights reserved.)- Published
- 2023
- Full Text
- View/download PDF