Developing a targeted therapy to enhance immune responses in NSD1-mutated squamous cell carcinoma

Presentation: S005
Topic: Cancer Biology
Type: Oral
Date: Sunday, July 9, 2023
Session: 10:45 AM - 12:15 PM Cancer Biology Session 1
Authors: Joanne Soo, MD1; Chen Chen, MD, PhD1; June Ho Shin, PhD1; Ravindra Uppaluri, MD, PhD2; Bruce Koch3; John B Sunwoo1
Institution(s): 1Department of Otolaryngology-Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA; 2Division of Otolaryngology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; 3Sarafan ChEM-H, Stanford University School of Medicine, Stanford, CA

While immunotherapy approaches like PD-1/PD-L1 immune checkpoint blockade have demonstrated durable responses in a wide range of advanced cancers, these dramatic responses are seen only in a subset of patients; the overall response rate of advanced head and neck squamous cell carcinoma (HNSCC) to immune checkpoint blockade is less than 20%. Approximately 15% of HNSCC, particularly tobacco-associated HNSCC, harbor an inactivating mutation in the H3K36-specific histone methyltransferase NSD1. Loss of NSD1 results in global hypomethylation of the genome and an “immune-cold” phenotype in which there is significantly reduced immune cell infiltration of the tumor microenvironment (TME). There is evidence that immune-cold tumors are resistant to immunotherapy and that enhancing immune infiltration into the TME can dramatically improve responses to immunotherapy.

Using in vitro and in vivo models, we investigated the effects of NSD1 inhibition on chemokine expression and T cell recruitment into the TME. In both human HNSCC tumor spheroids grown in submerged Matrigel, as well as murine MOC1 tumors grown in syngeneic immunocompetent mice, the inhibited expression of NSD1 by shRNA resulted in reduced expression of CXCL9 and CXCL10 and marked reduction in T cell infiltration. This correlation was also observed in clinical samples from previous HNSCC trial patients. Because the primary lysine demethylase targeting H3K36 in HNSCC is KDM2A, we investigated the potential of targeting KDM2A to reverse effects observed with NSD1 inactivation. The concomitant inhibition of KDM2A reversed the methylation marks on H3K36, increased expression of CXCL9 and CXCL10 and induced robust infiltration of T cells into the TME, pointing to KDM2A as a novel target to enhance immune responses. To this end, we have developed a time-resolved fluorescence energy transfer (TR-FRET) assay to screen over 160,000 small molecule compounds for inhibitors of KDM2A.

This assay was optimized to achieve a greater than 80% reduction in cost compared to commercially available assays. Active compounds identified through high-throughput screening will be optimized for bioavailability by medicinal chemistry approaches, with the goal of using these compounds to improve the response of patients with NSD1-mutated HNSCC and other malignancies to immunotherapy approaches, such as immune checkpoint blockade and cellular therapy.