Peripheral memory B cell population maintenance and long-term survival after perioperative chemoimmunotherapy in NSCLC (NADIM trial)

Abstract

B lymphocytes; Chemoimmunotherapy; Flow cytometry

Linfocitos B; Quimioinmunoterapia; Citometría de flujo

Limfòcits B; Quimioimmunoteràpia; Citometria de flux

Perioperative chemoimmunotherapy has significantly improved survival rates for non-small cell lung cancer (NSCLC). However, current tissue biomarkers remain inadequate, underscoring the need for more sensitive and accessible alternatives to monitor relapse risk. Intratumoral B-cells are increasingly recognized for their role in enhancing immunotherapy outcomes, yet the contribution of peripheral B-cells to immune surveillance remains unexplored. Peripheral B-cell immunophenotypes were analyzed from blood samples (at diagnosis, post-neoadjuvant, and at 6- and 12-months of adjuvant treatment) in 41 stage IIIA NSCLC patients treated with perioperative nivolumab plus chemotherapy, included in the NADIM clinical trial (NCT03081689). Results were correlated with 5-year survival outcomes and validated through unsupervised clustering. An increase in the percentage of total B-cells (CD19+CD20+) and naïve B-cells (CD19+CD20+CD24+CD38+CD27-CD10-), along with a reduction in CD20 expression on total B-cells, a decrease in the proportion of memory B-cells (CD19+CD20+CD24+CD38-/lowCD27+) and transitional B-cells (CD19+CD20+CD24++CD38++CD10+), was observed during the time encompassed between the end of neoadjuvant treatment and the posterior 6 months of adjuvant treatment. Higher levels of CD20 expression on total B-cells, along with an increased percentage of memory B-cells, or activated B-cells (CD19+CD20+CD25+), at 6- and 12-months of adjuvant treatment, were associated with increased survival. Conversely, higher levels of a newly described circulating population of CD19+CD20lowCD25lowCD27low B-cells during adjuvant treatment were linked to disease progression. Perioperative nivolumab plus chemotherapy in resectable NSCLC patients induces significant changes in peripheral B-cells. The persistence of circulating memory B-cells during adjuvant treatment might play a crucial role in survival.

Work in the authors’ laboratories was supported by “Instituto de Salud Carlos III” (ISCIII) PI19/01652 and PI22/01223 grants cofounded by European Regional Development Fund (ERDF), Bristol-Myers Squibb (BMS), Ministry of Science and Innovation RTC2017-6502-1 ‘INmunoSIGHT’, RTC2019-007359-1 ‘BLI-O’, CPP2022-009545 ‘STRAGEN-IO’, and European Union’s Horizon 2020 research and innovation programme, CLARIFY 875160 grant, to MP. AC-B is supported by a “Miguel Servet” contract CP23/00044 by ISCIII and received an ISCIII project grant PI23/01054 both cofounded by European Union. CM-T is supported by Comunidad de Madrid PIPF-2022/SAL-GL-25283 contract granted to MP. MM-A is supported by Ayuda Predoctoral Asociación Española Contra el Cáncer (AECC) Madrid 2023 contract granted to MP. AnG-G was supported by Comunidad de Madrid and European social fund PEJ-2023-AI/SAL-GL-27634 contract, and now is supported by FI24/00270 predoctoral contract from ISCIII granted to AC-B.