BCL2A1 and CCL18 Are Predictive Biomarkers of Cisplatin Chemotherapy and Immunotherapy in Colon Cancer Patients.

Abstract

Background: Cisplatin enhances the antitumor T cell response, and the combination of PD-L1 blockade produces a synergistic therapeutic effect. However, the clinical correlation between cisplatin and immunotherapy in colon cancer (CC) is unknown. Methods: Using the “pRRophetic” package, we calculated the IC50 of cisplatin. The correlation between cisplatin IC50, cisplatin resistance–related genes (CCL18 and BCL2A1), and immunotherapy were preliminarily verified in TCGA and further validated in independent cohorts (GSE39582 and GSE17538), cisplatin-resistant CC cell line DLD1, and our own clinical specimens. Classification performance was evaluated using the AUC value of the ROC curve. Scores of immune signatures, autophagy, ferroptosis, and stemness were quantified using the ssGSEA algorithm. Results: Based on respective medians of three CC cohorts, patients were divided into high- and low-IC50 groups. Compared with the high IC50 group, the low-IC50 group had significantly higher tumor microenvironment (TME) scores and lower tumor purity. Most co-signaling molecules were upregulated in low IC50 group. CC patients with good immunotherapy efficacy (MSI, dMMR, and more TMB) were more attributable to the low-IC50 group. Among seven shared differentially expressed cisplatin resistance–related genes, CCL18 and BCL2A1 had the best predictive efficacy of the above immunotherapy biomarkers. For wet experimental verification, compared with cisplatin-resistant DLD1, similar to PD-L1, CCL18 and BCL2A1 were significantly upregulated in wild-type DLD1. In our own CC tissues, the mRNA expression of CCL18, BCL2A1, and PD-L1 in dMMR were significantly increased. The high group of CCL18 or BCL2A1 had a higher proportion of MSI, dMMR, and more TMB. IC50, CCL18, BCL2A1, and PD-L1 were closely related to scores of immune-related pathways, immune signatures, autophagy, ferroptosis, and stemness. The microRNA shared by BCL2A1 and PD-L1, hsa-miR-137, were significantly associated with CCL18, BCL2A1, and PD-L1, and downregulated in low-IC50 group. The activity of the TOLL-like receptor signaling pathway affected the sensitivity of CC patients to cisplatin and immunotherapy. For subtype analysis, immune C2, immune C6, HM-indel, HM-SNV, C18, and C20 were equally sensitive to cisplatin chemotherapy and immunotherapy. Conclusions: CC patients sensitive to cisplatin chemotherapy were also sensitive to immunotherapy. CCL18 and BCL2A1 were novel biomarkers for cisplatin and immunotherapy.