AUTHOR=Yue Taohua , Liu Xiangzheng , Zuo Shuai , Zhu Jing , Li Jichang , Liu Yucun , Chen Shanwen , Wang Pengyuan 

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

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=Volume 9 - 2021

YEAR=2022

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.799278

DOI=10.3389/fcell.2021.799278

ISSN=2296-634X

ABSTRACT=Background: Cisplatin enhances the anti-tumor T cell response, and 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 “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 colon cancer 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 3 CC cohorts, patients were divided into high and low IC50 groups. Compared with high IC50 group, low IC50 group had significantly higher tumor microenvironment (TME) scores, lower tumor purity. Most co-signaling molecules were up-regulated in low IC50 group. CC patients with good immunotherapy efficacy (MSI, dMMR and more TMB) were more attributable to low IC50 group. Among 7 shared differentially expressed cisplatin resistance related genes, CCL18 and BCL2A1 had the best predictive efficacy of above immunotherapy biomarkers. For wet experimental verification, compared with cisplatin resistant DLD1, similar to PD-L1, CCL18 and BCL2A1 were significantly up-regulated in wild type DLD1. In our own CC tissues, the mRNA expression of CCL18, BCL2A1 and PD-L1 in dMMR were significantly increased. 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 down-regulated in low IC50 group. The activity of 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.