Abstract 3435: Spatial transcriptomic profiling reveals distinct tumor microenvironment remodeling patterns associated with immune checkpoint blockade response in lung adenocarcinoma

Abstract Although immune checkpoint blockade (ICB) has improved clinical outcomes in non-small cell lung cancer (NSCLC), many patients remain resistant, underscoring the need to understand how the tumor microenvironment (TME) evolves during therapy. Therefore, this study aims to characterize spatial TME remodeling associated with ICB. We performed 10x Genomics Visium spatial transcriptomic profiling on paired pre- and post-treatment tumor samples from seven patients with lung adenocarcinoma. Three patients were classified as responders based on immune Response Evaluation Criteria In Solid Tumors criteria (all stable disease) and were compared with four non-responders. The responder group received a mean of 13 ICB cycles, whereas non-responders received 2 cycles. Pre-treatment samples were obtained from lung (n = 4) and lymph node (n = 3), while post-treatment samples were collected from lung (n = 2), lymph node (n = 2), bone (n = 2), and brain (n = 1). After quality control, the mean number of spots was 2212, with a minimum of 266 spots, a maximum of 4715 spots, for a total of 30,968 spots. Spatial profiling demonstrated that responders exhibited consistently higher infiltration of plasma cells and B cells in both pre- and post-treatment samples. In contrast, non-responders showed increased proportions of cancer-associated fibroblasts (CAFs) at both time points. In the pre-treatment samples, responders showed upregulation of HLA-DMA and HLA-C, suggesting preservation of antigen presentation pathways. Additionally, IGKC, IGHG2, and IGHG1 were upregulated, indicating B-cell activation. Non-responders showed upregulation of extracellular matrix (ECM)-remodeling genes (TMSB4X, ACTB) and ferritin metabolism genes (FTL). In the post-treatment samples, non-responders also showed upregulation of ECM-remodeling genes (COL5A1, COL5A2, COL6A2, COL6A1, FN1, TIMP2, MMP2, MMP14), indicating enhanced tumor cell adaptation to a hostile microenvironment and a potential link to M2-like macrophage polarization. In summary, our findings demonstrate that ICB responders exhibit plasma/B-cell-enriched TMEs, whereas non-responders are characterized by increased CAF infiltration along with ECM remodeling and ferritin metabolism gene upregulation, suggesting a potential mechanism of immune resistance. We are currently validating the impact of this ferritin-associated ECM remodeling signature on ICB therapy outcomes in an independent cohort. Citation Format: Heesoo Yoon, Jin-Wook Choi, Sejoon Lee, Jin-Haeng Chung, Hyojin Kim. Spatial transcriptomic profiling reveals distinct tumor microenvironment remodeling patterns associated with immune checkpoint blockade response in lung adenocarcinoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3435.