Activation of the TGF-β Pathway Enhances the Efficacy of Platinum-Based Chemotherapy in Small Cell Lung Cancer Patients

Abstract

Background. Platinum-based chemotherapy is the first choice of treatment for patients diagnosed with small lung cell cancer (SCLC). However, many patients exhibit resistance to it. Therefore, it is imperative to further investigate a prognostic biomarker indicating sensitivity to this therapy. Methods. We collected and performed RNA sequencing on 45 SCLC samples from the Zhujiang Hospital (Local-SCLC). In addition, we used a public cohort from George et al. as a validation cohort (George-SCLC). The transforming growth factor β signaling pathway (TGFB) activation status was determined according to the related ssGSEA score. We analyzed immune cell ratios, pathway activation scores, and immune-related genes in SCLC patients to further elucidate the potential mechanisms. Results. A high activation status of the TGFB pathway was associated with improved prognosis in SCLC patients receiving platinum-based chemotherapy (Local-SCLC: $\text{HR}=0.0238$ , (95% CI, 0.13-0.84), $p=0.0238$ ; George-SCLC: $\text{HR}=0.0315$ , (95% CI, 0.28-0.98), $p=0.0315$ ). Immune infiltration analysis showed that the TGFB-HIGH group had more M1 macrophages and Th1 cells, whilst fewer M2 macrophages, Th2 cells, and Treg cells were found in the Local-SCLC cohort. Mechanistic analysis showed that the TGBF-HIGH group was upregulated in STING-mediated immunity, apoptosis, and cell cycle arrest, as well as being downregulated in the process of DNA damage repair. Conclusions. SCLC patients exhibiting a high activation status of the TGFB pathway demonstrate an improved prognosis with platinum-based chemotherapy. The potential underlying mechanism may be related to antitumor immune enhancement and DNA damage repair inhibition.