Abstract 7144: Integrative analysis of immunogenetics of the HLA-KIR-MIC system to predict clinical outcomes for checkpoint immunotherapy

Abstract Background: Immune-related adverse events (irAEs) have been associated with improved survival during checkpoint immunotherapy in thoracic cancers. However, the relationship between irAEs and survival across various solid tumors remains unclear. This study aims to validate the association between irAEs and prognosis in patients with solid tumors treated with immune checkpoint inhibitors (ICIs) and to identify predictive determinants of irAEs. Methods: This prospective observational cohort study included 138 patients with solid tumors receiving ICIs or chemo-ICIs, with a median follow-up of 27 months. The primary outcome was the association between irAEs and overall survival (OS). Clinically meaningful irAEs were defined as those requiring treatment delay or discontinuation of ICIs and/or systemic corticosteroids for management of toxic effects. High-resolution HLA/MIC/KIR genotyping and high-throughput plasma proteomics were performed from pre-ICI blood samples to identify determinants to predict irAEs. Results: Of the 138 patients, 43 (31%) developed irAEs. irAEs were more frequent among responders (12/20 CR (60%) and 4/7 PR (57%)) compared to those with SD (10/31 (32%)) and PD (17/80 (21%)). irAEs were associated with improved OS (median OS with irAEs: 25.8 mo.; without irAEs: 18.5 mo.; HR = 0.56 [95% CI, 0.33-0.95]) and disease-free survival (DFS) (median DFS with irAEs: 17.3 mo.; without irAEs: 4.8 mo.; HR = 0.49 [95% CI, 0.31-0.77]). Furthermore, patients with both durable clinical benefit (DCB) and irAEs demonstrated superior OS (median: 58 mo.) and DFS (median: 34.6 mo.) compared to DCB without irAEs (median OS: 33.4 mo.) and PD (median OS: 13.5 mo.; P = 1.5 × 10-6). Integrated immunogenetic analyses of HLA-A, -B, -C, -E, -F, -G, DRB1, DP, and DQ alleles, as well as MHC-I/II heterozygosity, Bw4/Bw6 (HLA-B), C1/C2 (HLA-C), and centromeric/telomeric KIR groups (AA vs. Bx), revealed distinct clusters for patient stratification. Patients with DCB and irAEs were enriched in more activating immunogenetic genotypes including Bw4 homozygosity, C2 homozygosity, and telomeric Bx KIR genotypes. Furthermore, proteomic analysis of pre-treatment plasma samples showed significant decreases in immunoregulatory proteins and cytokines in patients with DCB and irAEs. Multivariable regression analysis adjusted for cancer type and treatment modality demonstrated that integrative immunogenetics profiles (P=0.004) and circulating proteomic signatures (P=3.2x10-4) independently predicted benefit from ICIs while identifying patients at higher risk for irAE development. Conclusion: This study highlights the utility of integrating immunogenetics and systemic immunity profiling to stratify patients receiving ICIs. Blood-based biomarkers may predict clinical benefit and irAE development, warranting further prospective validation. Citation Format: Hyun-Sung Lee, Priyanka Ranchod, Sonali Mitra, Hee-Jin Jang, Claire Lee, Sung Wook Kang, Ji Seon Shim, Ito Atsushi, Gena Lee, Tannaz Armaghany, Michael Byrd, Aihua Yen, Quillan Huang, Rafee Talukder, Shalini Makawita, Benjamin Musher, Peter Jindra, Jinyoung Byun, Younghun Han, Daniel Wang, Bryan Burt, Meera Patel. Integrative analysis of immunogenetics of the HLA-KIR-MIC system to predict clinical outcomes for checkpoint immunotherapy [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 7144.