Reversible downregulation of HLA class I in adenoid cystic carcinoma

• DOI: 10.1136/jitc-2024-011380
• Publication Date: 2025-04-20T10:55:11Z
• Authors: Annie Li; Bianca L Gonda; Elizabeth M Codd; Adam von Paternos; Dawn R Mitchell; Markus D Herrmann; Prinjali Kalyan; Samantha E Flynn; Thuc Q Dzu; Chengzhuo Gao; Edwin Zhang; Julia J Mendel; Julia C Thierauf; Peter M Sadow; Thomas Denize; Diane Yang; Florian J Fintelmann; Jo Anne Fordham; Ross D Merkin; Atul K Bhan; Yu-Chung Huang; Jeffrey Raizer; William C Faquin; Daniel L Faden; Xin Gao; Jong Chul Park; Lori J Wirth; Stefan T Kaluziak; A. John Iafrate
• Keywords: Adenoid Cystic Carcinoma

Background Adenoid cystic carcinoma (ACC) is a rare, but lethal cancer with low response rates to systemic therapies, such as cytotoxic chemotherapy and immune-checkpoint inhibitors (ICIs). Despite extensive clinical trials, no effective treatments for patients recurrent or metastatic ACC are available, mortality remain poor. Methods We employed automated multiplex immunofluorescence (mIF), single-cell RNA sequencing (scRNA-seq) Gene Expression analysis, in-situ hybridization, spatial transcriptomics analysis characterize the immune landscape of tumors, metastasis, normal tissues from regions where ACCs arise. Based on results these studies, we treated freshly resected interferon-γ stimulator interferon genes (STING) agonist in vitro. Additionally, included one patient phase 1 study novel STING (dazostinag) plus pembrolizumab. Results The mIF revealed that tumors immunologically “cold”, few tumor-infiltrating T-lymphocytes programmed death-ligand (PD-L1) expression. most striking finding was very beta-2-microglobulin (B2M) expression nearly all ACCs, only focal found some metastases. analyses salivary gland breast p63+, NFIB+, basal duct cell population, similarly B2M/human leukocyte antigen (HLA) class I Spatial focally B2M-positive metastases uncovered genetic pathway driving upregulation B2M, an program mediating reintroduction HLA-I/B2M; significantly upregulated IRF1, GBP1, TAP1 . On short-term treatment primary vitro agonist, observed strongly HLA I/B2M Moreover, recurrent, pembrolizumab led partial 70% tumor reduction. Conclusions Low B2M/HLA may explain why cold lack ICIs. Our findings suggest origin exists B2M/HLA-class state, pharmacologic manipulation activators, agonists, can restore HLA/B2M supported by promising ACC. These indicate potential path urgently needed immunotherapies.