2024 Asia Conference on Lung Cancer (ACLC) - Poster & ePosters-PP01.59

PP01.59 - Zhengqi Cao

Pdf Summary

The study by Zhengqi Cao and colleagues at the Shanghai Lung Cancer Center explores the mechanisms behind resistance to neoadjuvant immunotherapy (neo-ICIs) in non-small-cell lung cancer (NSCLC). Although neo-ICIs have shown promising results with major pathological response rates between 20% to 50%, a significant percentage of patients do not respond, and the reasons for this remain unclear. Understanding these mechanisms is crucial for improving patient outcomes.<br /><br />The research employs advanced multi-omics approaches, such as single-cell RNA sequencing, digital spatial profiling, and bulk RNA sequencing, to analyze the tumor microenvironment, specifically focusing on cancer-associated fibroblasts (CAFs) in 37 NSCLC patients. The study identifies antigen-presenting CAFs (apCAFs) as key indicators of non-major pathological response, suggesting their involvement in immunotherapy resistance.<br /><br />The researchers discovered that apCAFs contribute to resistance by interacting with regulatory T cells (Tregs) through the PD-L2/RGMB axis. This interaction promotes the expansion of FOXP1 Tregs, which undermines the efficacy of immunotherapy. Experimental approaches, including 3D culture systems and murine models, revealed that blocking the PD-L2/RGMB axis can reverse the effects of apCAFs and improve the response to neo-ICIs.<br /><br />Moreover, the study demonstrates that anti-PD1 therapies can inadvertently promote apCAF expansion via the JAK1/2-STAT1-IFI6/27 pathway, further complicating the treatment landscape. By targeting the PD-L2/RGMB interaction, it is possible to reduce FOXP1 Treg expansion and thus enhance the effectiveness of immunotherapy.<br /><br />This research provides valuable insights into potential targets for overcoming immunotherapy resistance in NSCLC, offering a promising avenue for improving treatment strategies and broadening the range of patients who can benefit from neo-ICIs.

Keywords

neoadjuvant immunotherapy

NSCLC

immunotherapy resistance

multi-omics

cancer-associated fibroblasts

PD-L2/RGMB axis

FOXP1 Tregs

single-cell RNA sequencing

tumor microenvironment

anti-PD1 therapies