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

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 inacti-vation results in lower levels of H3K36 dimethylation and higher levels of H3K27 trimethylation, the latter being a known repres-sive 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 suppres-sion decreased growth of NSD1-deficient tumors in immuno-competent, 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.