Abstract
Abstract While immune checkpoint blockade (ICB) induces durable cancer remission, only a small subset of patients can receive benefits, whereas a substantial portion of patients encounter severe immune-related adverse events. Further, about 4-29% of patients experience dramatic acceleration of disease progression after ICB treatment. Predictive biomarkers of ICB responses are in high demand to ensure patient benefits and avoid tragic clinical outcomes. In addition to PD-L1 tests, several genetic biomarkers are associated with ICB effectiveness, such as tumor mutation burden (TMB), somatic copy number aberrations, indels, and microsatellite instability. However, none of these neoantigen markers are sufficient to discriminate ICB responders in diverse cancer entities of distinct genetic profiles. In particular, TMB fails to predict in the cancer types with low simple mutation rates, such as triple-negative breast cancer (TNBC), ovarian cancer, and esophageal cancers. In TNBC, high TMB only accounts for 5-10% of patients, whereas a much larger proportion of tumors are inflamed (26-50%), which suggests a possible uncharacterized major source of neoantigens. Similarly, TMB is not predictive of ICB response in ovarian cancers according to the IMagyn050 trial. In esophageal cancer, TMB is not associated with T cell infiltration and does not predict ICB response. Our analyses of Pan-cancer whole genomes revealed that intragenic rearrangement (IGR) burden is a pivotal contributor to immune infiltration in breast, ovarian, esophageal, and endometrial cancers, which correlates with increased Macrophage M1 and CD8+ T cell signatures. IGRs result in exon duplications or deletions through rearrangements of a genomic distance of tens of kilobases. Multivariate regression against spatially counted tumor infiltrated lymphocytes in breast, endometrial, and ovarian cancers suggest that IGR burden is a more influential covariate than other genetic aberrations in these cancers. In the MEDI4736 trial evaluating durvalumab in esophageal adenocarcinoma, IGR burden correlates with patient benefits. In the IMVigor210 trial evaluating atezolizumab in urothelial carcinoma, IGR burden increases with platinum exposure and predicts patient benefits for TMB-low, platinum-exposed tumors. Altogether, we demonstrate that IGR burden contributes to T-cell inflammation and predicts ICB benefits in TMB-low, IGR-dominant tumors, or in platinum-exposed tumors. IGRs as a cryptic class of structural variants have been heretofore overlooked in cancer genomics studies. The association of IGRs with ICB response has not been previously reported in cancer in general. The development of IGR burden-based predictive marker could increase effectiveness of ICB therapy, reduce severe side-effects and unnecessary costs. Citation Format: Han Zhang, Sanghoon Lee, Renee R. Muthakana, Binfeng Lu, David N Boone, Daniel Lee, Xiaosong Wang. Associations of intragenic rearrangement burden with immune cell infiltration and response to immune checkpoint blockade in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3861.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.