Abstract 749: Dynamic change in immune landscape among NSCLC patients who received neo-adjuvant PD-1 treatment

Abstract Background: Neoadjuvant immunotherapy in combination with chemotherapy has been approved for resectable lung squamous cell carcinoma (LUSC) patients. However, the dynamic protein changes in the local tumor microenvironment (TME) associated with treatment remains unclear. We sought to spatially profile the treatment-related protein landscape changes in LUSC. Methods: A total of 11 LUSC patients who received 2 to 4 cycles of neoadjuvant PD-1 inhibitors in combination with chemotherapy (nab-paclitaxel and carboplatin) were recruited. Formalin-fixed paraffin-embedded (FFPE) pre-treatment lung biopsy and paired post-operative surgery samples were collected. To investigate the immune landscape change related to neoadjuvant immunotherapy, we utilized the GeoMx Digital Spatial Profiler (DSP) to spatially profile the expression of >570 proteins in tumor- (pan-CK+), immune- (CD45+), and cancer-associated fibroblast (CAF, a-SMA+) regions in pre- and post-treatment specimens. Differential expression analyses, and GSEA were performed. Results: We found that active YAP1, BAX, and IRF3 in the tumor region, and CD11a, CXCR3, and CD34 in the immune region were upregulated after treatment, while Syndecan-1, Tuberin, and PAK1 in the immune region and MEK1, CD3G, and VEGFD in the CAF region were downregulated after treatment (all FDR < 0.05). GSEA highlighted that the neoadjuvant immunochemotherapy downregulated differentiation, HIF1, Insulin, and mTOR pathway (NES: -1.70, -1.76, -1.77, and -1.64, respectively) in immune and CAF regions (all adjusted P < 0.05). Findings suggested that neoadjuvant immunochemotherapy may improve oxygenation via the HIF1 pathway, induce metabolic stress and nutrient depletion via the mTOR and insulin pathways, promote dedifferentiation or epithelial-to-mesenchymal transition, as well as reduce immune evasion by modifying the tumor microenvironment. This study provides clues and preliminary evidence to further understand the treatment mechanism of neoadjuvant immunochemotherapy for LUSC. Conclusion: In this spatial biology study, we found dynamic changes in proteins between pre- and post-neoadjuvant immunochemotherapy among LUSC patients. The dynamic changes revealed some potential impacts of NAT on LUSC, including improving oxygenation, reducing mTOR and insulin activity, and mitigating immune evasion. Understanding these mechanisms can guide the development of combination therapies to improve patient outcome. Citation Format: Zheshen Han, Haoting Shi, Xue Wang, Yufei Wang, Ruixin Pan, Chao Hu, Qing Qu, Rong Cai. Dynamic change in immune landscape among NSCLC patients who received neo-adjuvant PD-1 treatment [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 749.