Abstract 4542: B cells mediate antitumor immune response and predict pathological response in locally advanced NSCLC patients treated with perioperative chemoimmunotherapy (NADIM trials)

Perioperative chemoimmunotherapy (ChIO) has become a paradigm shift in the treatment of patients with locally advanced non-small cell lung cancer (NSCLC), considerably increasing complete pathological response (CPR) and survival rates. The role played by B lymphocytes in the antitumor response emerges as a crucial factor in the fight against cancer, although mechanisms remain to be elucidated. Therefore, the main objective of this study is the identification of B lymphocyte-related mechanisms and biomarkers of response to perioperative chemoimmunotherapy treatment in patients with locally advanced NSCLC. For this purpose, tumor tissue B-cell receptor (BCR) repertoire, gene expression profile by bulk RNA sequencing, and qualitative localization by spatial transcriptomics have been characterized in 110 NSCLC patients receiving ChIO from NADIM and NADIM II trials (NCT03081689 and NCT03838159). Results of this work show an association between CPR and neoadjuvant treatment with a more diverse (p=0.069) and less even (p=0.030) BCR repertoire in pre-treatment tissue, which appears to be dominated by a set of more frequent clones (top 10, p=0.043). In addition, neoadjuvant chemoimmunotherapy induced overexpression of B lymphocyte-related genes in surgical tissue, mainly localized at tertiary lymphoid structures (TLSs) identified by spatial transcriptomics. Those tumors with low BCR repertoire evenness (CPR response) exhibited a different gene expression profile compared to highly even tumors (non-CPR). TLSs area and density were higher in CPR/low evenness sample compared to NCPR/high evenness; and functional T helper lymphocytes, defined as T CD4 lymphocytes colocalized with antigen presentation genes, were detected only in CPR/low evenness sample. In conclusion, tumor BCR repertoire clonality is associated to CPR after neoadjuvant ChIO. Neoadjuvant ChIO induces expression of B cell related genes in the context of TLS, being their area and functionality dependent on baseline BCR repertoire clonality. Citation Format: Belen Sierra-Rodero, Cristina Martínez-Toledo, Marta Molina-Alejandre, Ángeles Gil-González, Ernest Nadal, Alex Martinez-Marti, Bartomeu Massuti, Amelia Insa, Joaquín Casal, Javier de Castro, Rosario García Campelo, José Luis González-Larriba, Reyes Bernabé, Santiago Ponce, Manuel Dómine, Noemí Reguart, Carlos Camps, Guillermo López Vivanco, Manuel Cobo, Virginia Calvo, Ana Collazo-Lorduy, Mariano Provencio, Alberto Cruz-Bermúdez. B cells mediate antitumor immune response and predict pathological response in locally advanced NSCLC patients treated with perioperative chemoimmunotherapy (NADIM trials) [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 4542.