Tumor‐derived Vimentin as a novel biomarker for distinct subtypes predicting adjuvant chemotherapy resistance and T‐cell‐inflamed phenotype in small cell lung cancer

Despite recent progress in subtype classification for small cell lung carcinoma (SCLC), little is known about the biomarker for triple‐negative (ASCL1, NEUROD1, and POU2F3 negative) tumors. The long‐term survival, adjuvant chemotherapy (ACT) response, and immune milieu in different SCLC subtypes have also not been well established. Here, we retrospectively collected a large cohort of 192 primary SCLC tumors and reported that ASCL1‐, NEUROD1‐ and POU2F3‐dominant subtypes counted for 61.38%, 19.31%, and 6.21%, respectively. Subtype intra‐tumoral heterogeneity and co‐expression at the single‐cell level existed substantially. The expression of tumor‐derived Vimentin (VIM) was nearly restricted to triple‐negative SCLC tumors (15/19, 78.9%) while YAP1 expression was distributed widely in other subtypes. The SCLC subtyping model was independently prognostic of OS and RFS (p < 0.001 and p = 0.043). In particular, patients with ASCL1‐positive SCLC tumors can benefit more from ACT, and VIM‐positive tumors did the opposite. Compared with other subtypes, the VIM‐dominant SCLC subtype was associated with abundant but functionally impaired CD4(+) and CD8(+) T‐cells, which highly expressed inhibitory checkpoints and potentially benefit from PD‐L1 blockade therapy. Our study showed that tumor‐derived SCLC‐V subtype could independently predict ACT response. The distinct immune landscape between subtypes may help inform personalized immune therapeutic approaches.