Abstract 2059: High intratumoral heterogeneity and altered immune microenvironment associated with 11q13 amplification in Chinese NSCLC implications for hyperprogressive disease

Abstract Background: Immune checkpoint inhibitors have revolutionized the treatment landscape for non-small cell lung cancer (NSCLC), but a subset of patients experiences hyperprogressive disease (HPD) following immunotherapy. Previous studies indicate a potential link between specific genetic alterations and HPD. This study aims to investigate the role of the 11q13 chromosomal amplification, encompassing genes CCND1, FGF3, FGF4, and FGF19, in contributing to immunotherapy resistance and the occurrence of HPD in NSCLC patients. Methods: We performed comprehensive genomic analyses on tumor specimens from 12, 682 NSCLC patients using a next-generation sequencing (NGS) panel of 733 genes, alongside multiplex immunofluorescence assessments to characterize the immune microenvironment. Gene mutation profiles, tumor mutation burden (TMB), intratumoral heterogeneity (ITH), and immune cell infiltration profiles of 11q13 amplified and non-amplified patients were analyzed. Results: Among these patients, we identified 208 cases with 11q13 amplification. Analysis revealed that patients without 11q13 amplification exhibited higher mutation frequencies in key DNA damage repair (DDR) pathway genes, including ATR (10.1%), ATM (8.65%), MSH3 (7.21%), and others, compared to patients with 11q13 amplification. Notably, TMB was significantly elevated in 11q13-amplified patients (P<0.001), contradicting the expected positive correlation between high TMB and better immunotherapy outcomes. Furthermore, ITH was significantly higher in the 11q13-amplified cohort (P<0.001), indicating greater tumor heterogeneity, which has been associated with poorer immunotherapeutic responses. Immune microenvironment analysis demonstrated a significantly decreased presence of CD68+ HLA-DR+ M1 tumor-associated macrophages (TAM) in the tumors of 11q13-amplified patients. In contrast, there was an elevated frequency of CD3+CD4+FOXP3+ regulatory T cells (Treg) in the tumor stroma of these patients, aligning with prior findings suggesting Treg involvement in HPD. Conclusion: Our findings underscore that the 11q13 chromosomal amplification is associated with a unique genomic and immunological profile in NSCLC patients, characterized by high ITH and altered immune microenvironments, which may contribute to the development of HPD following immunotherapy. These insights highlight the potential need for tailored therapeutic strategies that address the specific challenges posed by 11q13 amplification in NSCLC. Citation Format: Zuoqing Song, Yifan Yifan Zhang, Hao Zhang. High intratumoral heterogeneity and altered immune microenvironment associated with 11q13 amplification in Chinese NSCLC implications for hyperprogressive disease [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 2059.