Targeting KDM2A Enhances T Cell Infiltration in NSD1-Deficient Head and Neck Squamous Cell Carcinoma. Cancer research Chen, C., Shin, J. H., Fang, Z., Brennan, K., Horowitz, N. B., Pfaff, K. L., Welsh, E. L., Rodig, S. J., Gevaert, O., Gozani, O., Uppaluri, R., Sunwoo, J. B. 2023


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 immununosuppression. Here, we demonstrated that NSD1 inactivation results in lower levels of H3K36 di-methylation and higher levels of H3K27 tri-methylation, 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.

View details for DOI 10.1158/0008-5472.CAN-22-3114

View details for PubMedID 37311054