Predictive role of immune cell subsets and intestinal flora in immune-related adverse event of small cell lung cancer.

Abstract

8112 Background: While immune checkpoint inhibitors (ICIs) have reshaped the therapeutic landscape for extensive-stage small-cell lung cancer (ES-SCLC), they are frequently associated with immune-related adverse events (irAEs) that may lead to treatment disruption. Early prediction of irAEs remains challenging due to their atypical clinical manifestations. This study aimed to identify risk factors and predictive biomarkers for irAEs in ES-SCLC patients undergoing ICIs therapy. Methods: 88 patients with ES-SCLC who received ICIs treatment between May 2021 and September 2023 were enrolled. Fecal samples were collected at baseline and before each treatment cycle until therapy discontinuation. The metagenomic and untargeted metabolomic analyses were performed on the fecal samples. Peripheral blood samples were collected from patients for flow cytometry analysis. Tumor response was assessed in accordance with RECIST 1.1 criteria, and irAEs were graded based on the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Results: Among 88 patients, 41 developed irAEs (median onset: 118 days), with the most common manifestations being pneumonia (41.5%) and hepatitis (22.0%). Patients who developed irAEs exhibited distinct peripheral immune profiles. Compared to their own baseline levels, these patients exhibited decreased peripheral B-cell counts alongside elevated percentages of activated CD4 + and CD8 + T cells, including early-activated CD8 + T cells (CD3 + CD8 + CD69 + T cells), late-activated helper T cells (CD3 + CD4 + CD38 + T cells), and Th2 cells. Furthermore, at baseline, the irAE group demonstrated a significantly higher percentage of PD-1 in CD8 + T cells compared to the non-irAE group. Metabolomic analyses revealed distinct baseline metabolic profiles between the two groups, Micrococcus was significantly enriched at baseline in the irAE group, whereas Phocaeicola coprocola and Oscillibacter were more abundant in patients without irAEs, and calcitriol was identified as a potential predictive biomarker for irAEs. Following irAE onset, significant enrichment of Selenomonadaceae , Ruminococcus , Actinobacteria , and Erysipelatoclostridium was observed, along with significant shifts in metabolites and related metabolic pathways. Conclusions: In ES-SCLC patients treated with ICIs, the development of irAEs is associated with distinct alterations in peripheral immune cell subsets, as well as gut microbial and metabolic profiles at baseline. Monitoring these features, particularly PD-1 expression on CD8+ T cells and calcitriol levels, may help predict the risk of irAEs. Dynamic changes in the gut microbiome and metabolome after ICIs initiation further aid in the early recognition of irAEs.