Abstract 7245: Reversible downregulation of HLA class I in adenoid cystic carcinoma

Abstract Background: Adenoid cystic carcinoma (ACC), a rare and lethal cancer, has shown low response rates to systemic therapies, such as cytotoxic chemotherapy, tyrosine kinase inhibitors and immune-checkpoint inhibitors (ICIs). Despite numerous clinical trials, no effective treatments for patients with recurrent or metastatic ACC have emerged, and ACC mortality rates remain stagnant. Therefore, we aimed to characterize the ACC immune landscape to understand the poor response rates to ICIs. Experimental Design: We leveraged automated multiplex immunofluorescence (mIF), RNA in-situ hybridization, scRNAseq Gene Expression analysis and spatial transcriptomics analysis to identify pathways supporting the cold ACC immune environment and molecularly characterize ACC tumors, ACC metastasis, adjacent normal tissues, and normal tissues from regions where ACCs arise. Based on results from these studies, we treated freshly resected ACCs with interferon-γ or a STING agonist in vitro. Results: mIF demonstrated that ACC tumors are immunologically ‘cold’, with few tumor-infiltrating T-lymphocytes (TILs) and low PD-L1 expression. The most striking finding, however, was a very low B2M expression in almost all ACCs, with focal expression found in some metastatic cases. Spatial transcriptomics of these focally B2M-positive ACC metastases further identified significantly upregulated genes, including IRF1, GBP1 and TAP1, indicating an interferon-γ program that mediated reintroduction of HLA-I/B2M. Upon short-term treatment of primary ACC tissues in vitro with interferon-γ or a STING agonist, we observed strongly upregulated HLA/B2M class I expression. mIF and RNAseq analyses of normal salivary gland and breast tissues revealed a p63+, NFIB+, basal duct cell population with similarly low B2M/HLA class I expression. Conclusions: Low B2M/HLA class I expression may explain why ACCs are immunologically cold and the lack of response to ICIs. Our findings suggest that the normal cell of ACC origin exists in a B2M/HLA-class I low state, and that pharmacologic manipulation with immune activators, such as STING agonists, can restore HLA/B2M in ACCs, creating a path to urgently needed, effective immunotherapies. Citation Format: 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, Chengzhou Gao, Edwin Zhang, Julia J. Mendel, Julia C. Thierauf, Peter M. Sadow, Thomas Denize, Diane Yang, Florian J. Fintelmann, Ross D. Merkin, Atul K. Bhan, William C. Faquin, Daniel L. Faden, Xin Gao, Jong Chul Park, Lori J. Wirth, Stefan T. Kaluziak, Anthony John Iafrate. Reversible downregulation of HLA class I in adenoid cystic carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7245.