A random survival forest-based pathomics signature classifies immunotherapy prognosis and profiles TIME and genomics in ES-SCLC patients

Background Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor with high mortality, and only a limited subset of extensive-stage SCLC (ES-SCLC) patients demonstrate prolonged survival under chemoimmunotherapy, which warrants the exploration of reliable biomarkers. Herein, we built a machine learning-based model using pathomics features extracted from hematoxylin and eosin (H&E)-stained images to classify prognosis and explore its potential association with genomics and TIME. Methods We retrospectively recruited ES-SCLC patients receiving first-line chemoimmunotherapy at Nanjing Jinling Hospital between April 2020 and August 2023. Digital H&E-stained whole-slide images were acquired, and targeted next-generation sequencing, programmed death ligand-1 staining, and multiplex immunohistochemical staining for immune cells were performed on a subset of patients. A random survival forest (RSF) model encompassing clinical and pathomics features was established to predict overall survival. The function of putative genes was assessed via single-cell RNA sequencing. Results and conclusion During the median follow-up period of 12.12 months, 118 ES-SCLC patients receiving first-line immunotherapy were recruited. The RSF model utilizing three pathomics features and liver metastases, bone metastases, smoking status, and lactate dehydrogenase, could predict the survival of first-line chemoimmunotherapy in patients with ES-SCLC with favorable discrimination and calibration. Underlyingly, the higher RSF-Score potentially indicated more infiltration of CD8 + T cells in the stroma as well as a greater probability of MCL-1 amplification and EP300 mutation. At the single-cell level, MCL-1 was associated with TNFA-NFKB signaling and apoptosis-related processes. Hopefully, this noninvasive model could act as a biomarker for immunotherapy, potentially facilitating precision medicine in the management of ES-SCLC.