Abstract 7349: Impact of HLA loss on NK cell infiltration and resistance to immunotherapy

Abstract Background: Clinical resistance to immunotherapy remains a significant challenge in cancer treatment, with many patients requiring combination therapies to achieve optimal therapeutic outcomes. Tumor cells often evade immune detection by down-regulating Major Histocompatibility Complex (MHC)-I or Human Leukocyte Antigen (HLA) expression, effectively escaping T-cell-mediated immunity. However, this loss may enhance tumors susceptible to Natural Killer (NK) cells, which are capable of recognizing and targeting cells with diminished HLA expression. Elucidating the interplay between HLA heterogeneity, NK cell infiltration, and the tumor immune microenvironment (TIME) is critical for addressing resistance and improving immunotherapy efficacy. This study investigates the HLA loss and its impact on tumor-infiltrating NK cells in the TIME. Methods: Utilizing single-cell RNA-seq data from human pan-cancer datasets, we crafted 18 distinct pan-cancer NK signatures reflective of NK presence. Pan-cancer datasets, including lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD), were analyzed using gene set enrichment analysis (GSEA), correlation heatmaps, and survival analyses to evaluate NK cell activity, HLA expression, and immune microenvironment characteristics. The T and NK cell ratio was explored as a potential biomarker of HLA heterogeneity. Linear Discriminant Analysis (LDA) was also employed to evaluate the separation of high and low NK activity groups, though these results were inconclusive. Results: HLA loss patients exhibited increased NK cell infiltration, likely driven by diminished inhibitory signaling in the absence of HLA molecules. Significant correlations between the T and NK cell ratio and HLA heterogeneity were observed, suggesting its potential as a biomarker for immune profiling. High NK activity was associated with improved survival outcomes, underscoring the protective role of NK cells in the TIME. Hot tumors showed higher NK cell infiltration and lower HLA heterogeneity compared to cold tumors, highlighting distinct patterns of immune cell recruitment. Conclusion: Tumor-infiltrating NK cells represent a promising target for overcoming therapy resistance associated with HLA loss. Although the LDA results were inconclusive, the observed associations between NK signatures, HLA heterogeneity, and the T and NK cell ratio lay a solid foundation for further investigation. These findings suggest that NK cells and the T and NK ratio could serve as both biomarkers and therapeutic targets in immunotherapy-resistant cancers. Future studies should validate these findings across independent datasets and explore NK-targeted combination therapies. Citation Format: Olamide Adefioye, Youngsoo Han, Lucas Yeung, Aidan Shen, Jesse Wang, Zhaohui Wang, Cheng-chi Chao, Chongming Jiang. Impact of HLA loss on NK cell infiltration and resistance to 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 7349.