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The autoimmune regulator (AIRE) induces the transcription of thousands of peripheral tissue genes (PTGs) in thymic epithelial cells (TECs) to mediate immunological tolerance. The chromatin state required for optimal AIRE function in TECs and how this state is induced remains unclear. We tested the role of the histone acetyltransferase, KAT7 (also known as HBO1 or MYST2), which is essential for acetylation of histone 3 lysine 14, in TEC differentiation, AIRE-mediated PTG expression, and thymic tolerance. We find that KAT7 is required for optimal expansion of medullary TEC and has a major role in the expression of AIRE-dependent PTGs, associated with enhanced chromatin accessibility at these gene loci in TECs. Mice with TEC-specific Kat7 deletion develop organ-specific autoimmunity with features resembling those observed in Aire-deficient mice. These findings highlight critical roles for KAT7-mediated acetylation in promoting a chromatin state at PTG loci that enables AIRE function and the establishment of immunological tolerance. [ABSTRACT FROM AUTHOR]

Skin-resident CD8 + T cells include distinct interferon-γ-producing [tissue-resident memory T type 1 (T RM 1)] and interleukin-17 (IL-17)-producing (T RM 17) subsets that differentially contribute to immune responses. However, whether these populations use common mechanisms to establish tissue residence is unknown. In this work, we show that T RM 1 and T RM 17 cells navigate divergent trajectories to acquire tissue residency in the skin. T RM 1 cells depend on a T-bet-Hobit-IL-15 axis, whereas T RM 17 cells develop independently of these factors. Instead, c-Maf commands a tissue-resident program in T RM 17 cells parallel to that induced by Hobit in T RM 1 cells, with an ICOS-c-Maf-IL-7 axis pivotal to T RM 17 cell commitment. Accordingly, by targeting this pathway, skin T RM 17 cells can be ablated without compromising their T RM 1 counterparts. Thus, skin-resident T cells rely on distinct molecular circuitries, which can be exploited to strategically modulate local immunity.

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., 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.)