Immune exclusion driven by myeloid cells contributes to resistance to checkpoint inhibitor and anti-angiogenic therapy in NSCLC 4771

Abstract Description Suppressive immune cells and their associated cytokines and chemokines promote vascular endothelial proliferation and malformation, hindering immune cell penetration into the tumor core. In a phase II trial combining bevacizumab with atezolizumab in metastatic NSCLC patients (with a disease control rate of 87.5%) whose disease progressed after atezolizumab monotherapy, we analyzed blood biomarker changes collected at baseline, one week post-therapy, and at disease progression. Myeloid cells, including neutrophils, PMN-MDSCs, and M-MDSCs, were significantly correlated with responses to therapy. Durable responders exhibited high CXCL5 levels (p = 0.005) in blood. Additionally, lower neutrophil-to-lymphocyte ratios (p = 0.022), PMN-MDSCs (p = 0.036), and PD1+CD8+ T cells (p > 0.001) were associated with improved overall survival. Lower levels of suppressive proteins, including TCTP (p = 0.013), IL-6 (p < 0.001), IL-18 (p = 0.03), VEGF-A (p < 0.001), TIE-2 (p = 0.06), PD-L2 (p = 0.041), and CD147 (p = 0.008), were associated with better survival outcomes, highlighting their roles in therapy resistance. In vivo, vascular malformation and immune cell exclusion were prominent, with differential immune cell distribution between the tumor core and edge depending on hypoxia and vascular abnormalities. Combination therapy reduced suppressive and exhausted immune cells. These findings underscore the role of myeloid cells and factors such as IL-6, TCTP, and VEGF-A in resistance to therapy. Funding Sources This research was supported by NRF (National Research Foundation of Korea) funded by the Korean Government (RS-2022-NR075028) Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)