Targeting KDM2A Enhances T-cell Infiltration in NSD1-Deficient Head and Neck Squamous Cell Carcinoma.

Autor:	Chen C; Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, California.; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California., Shin JH; Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, California.; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California., Fang Z; Department of Anesthesia, Pain and Perioperative Medicine, Stanford University School of Medicine, Stanford, California., Brennan K; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.; Department of Medicine (Biomedical Informatics) and Department of Biomedical Data Sciences, Stanford University School of Medicine, Stanford, California., Horowitz NB; Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, California.; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California., Pfaff KL; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts., Welsh EL; Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts., Rodig SJ; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.; Dana-Farber Cancer Institute, Boston, Massachusetts., Gevaert O; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.; Department of Medicine (Biomedical Informatics) and Department of Biomedical Data Sciences, Stanford University School of Medicine, Stanford, California., Gozani O; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.; Department of Biology, Stanford University, Stanford, California., Uppaluri R; Dana-Farber Cancer Institute, Boston, Massachusetts.; Division of Otolaryngology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts., Sunwoo JB; Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, California.; Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2023 Aug 15; Vol. 83 (16), pp. 2645-2655.
DOI:	10.1158/0008-5472.CAN-22-3114
Abstrakt:	In head and neck squamous cell carcinoma (HNSCC), a significant proportion of tumors have inactivating mutations in the histone methyltransferase NSD1. In these tumors, NSD1 inactivation is a driver of T-cell exclusion from the tumor microenvironment (TME). A better understanding of the NSD1-mediated mechanism regulating infiltration of T cells into the TME could help identify approaches to overcome immunosuppression. Here, we demonstrated that NSD1 inactivation results in lower levels of H3K36 dimethylation and higher levels of H3K27 trimethylation, the latter being a known repressive histone mark enriched on the promoters of key T-cell chemokines CXCL9 and CXCL10. HNSCC with NSD1 mutations had lower levels of these chemokines and lacked responses to PD-1 immune checkpoint blockade. Inhibition of KDM2A, the primary lysine demethylase that is selective for H3K36, reversed the altered histone marks induced by NSD1 loss and restored T-cell infiltration into the TME. Importantly, KDM2A suppression decreased growth of NSD1-deficient tumors in immunocompetent, but not in immunodeficient, mice. Together, these data indicate that KDM2A is an immunotherapeutic target for overcoming immune exclusion in HNSCC. Significance: The altered epigenetic landscape of NSD1-deficient tumors confers sensitivity to inhibition of the histone-modifying enzyme KDM2A as an immunotherapeutic strategy to stimulate T-cell infiltration and suppress tumor growth. (©2023 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu