Abstract A055: Dissecting mechanisms of tumor anti-PD1 resistance due to host genetic variation within ADAM17

Abstract Clinical application of anti-PD1 or anti-PDL1 antibodies, also known as Immune checkpoint blockade (ICB) therapy, has shown potential as an anti-cancer treatment. However, currently only 10 to 30 percent of cancer patients responds to ICB. Successful ICB treatment depends on a variety of factors including tumor mutation burden, cancer subtype, and patient genetics, the latter of which is currently understudied. Therefore, there is a clear need to understand how host genetics influences ICB clinical success to improve patient outcomes. Our laboratory primarily focuses on the study of transforming growth factor-beta (TGFβ) signaling across a variety of disease contexts. We have generated two congenic mouse strains that harbor either NIH or C57 genomic DNA at the proximal end of chromosome 12 NIH/Ola that differentially regulate TGFβ signaling. The C57 congenic region, include variant tumor necrosis-alpha converting enzyme (TACE, encoded by Adam17). Utilizing these congenic mice in syngeneic cancer models, we generated preliminary data suggesting that C57 “hypoactive” Adam17 variant (with two non-synonymous SNPs at D113N and I613V) correlates with better response to ICB compared to congenic mice that harbor NIH Adam17 allele, which are resistant to ICB therapy. Considering the discrepancy in both ICB response and ADAM17 activity, we employed a Wyeth developed highly specific small molecule inhibitor of TACE (TMI-2) in vivo and found it can resensitize ICB resistant mice to ICB treatment, suggesting that ADAM17 activity may suppress ICB efficacy. We have also performed initial immunotyping analysis on ICB these sensitive and resistant congenic mice, with and without ICB, and have found differences in myeloid and T cell infiltrate into the tumor microenvironment, suggesting that ADAM17 may regulate the tumor microenvironment landscape. We have preliminary in vitro data suggesting that hypoactive variants of T cell ADAM17 may reduce T cell death through inhibition of release of tumor necrosis factor alpha, which is known to induce T cell death via TNFR1. This study provides support for utilizing ADAM17 as a therapeutic target for patients who harbor ICB resistant cancers and provides potentially invaluable insights into the consequences of ADAM17 activity in T cell dependent tumor biology. Citation Format: James P Heiserman, Rosemary Akhurst, Tanuja Desai, Sharon Chen. Dissecting mechanisms of tumor anti-PD1 resistance due to host genetic variation within ADAM17 [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A055.