Dissecting mechanisms of tumor immune checkpoint blockade resistance due to host genetic variation within Adam17

Clinical application of anti-PD-1 or anti-PDL-1 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 respond to ICB. Successful ICB treatment depends on a variety of factors including tumor mutation burden, cancer subtype, and patient germline genetics. 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 (TGF-beta) signaling across a variety of disease contexts. We have generated two paired congenic NIH/Ola mouse strains that harbor either NIH/Ola or C57Bl/6J across the Tgfbm3b locus on proximal chromosome mouse 12. Tgfbm3b is known to modulate TGFbeta signaling and encompasses genetic variants of tumor necrosis-alpha converting enzyme (TACE, also known as ADAM17). Utilizing these congenic mice implanted with syngeneic cancer cells, we generated preliminary data suggesting that the C57 “hypoactive” allele of Adam17 , with amino acid variation at D113N, I613V, correlates with better response to ICB compared to congenic mice that harbor the active NIH allele, which are resistant to ICB treatment. Considering that inheritance of hypoactive Adam17 enhances ICB response, we employed a highly specific small molecule inhibitor of TACE (TMI-2) finding that it sensitizes ICB-resistant tumors to immunotherapy across two in vivo syngeneic squamous cell carcinoma (SCC) models, suggesting that ADAM17 activity may suppress ICB efficacy. We have detailed the immune cell infiltrate on ICB sensitive and resistant mouse models, with and without ICB, using both flow cytometry and RNA sequencing techniques, and have found differences in myeloid and T cell infiltrate into the tumor microenvironment, suggesting that ADAM17 may regulate the tumor microenvironment landscape. We also have in vitro data suggesting that hypoactive variants of ADAM17 may reduce immune cell secretion of Tumor Necrosis Factor Alpha (TNFalpha) and TNFalpha induced cell death in specific immune cell types. TMI-2 is safe in humans, and this study provides support for targeting ADAM17 as a therapeutic target for patients who harbor ICB resistant cancers. The study also provides invaluable insights into the cell-type specific consequences of ADAM17 activity in tumor biology and highlights the need to consider patient genetics when applying ICB therapy.