Immune Checkpoint-Related Gene Polymorphisms and High Serum Concentration of PD-L1 and CTLA4 Contribute to the Resistance to Platinum-Based Chemotherapy in Cervical Cancer

Hongqin Yuan,* Xinfeng Wang,* Kaidong Liu, Jia Zhang, Pei Wang Department of Radiotherapy, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, 030013, People’s Republic of China*These authors contributed equally to this workCorrespondence: Pei Wang, Department of Radiotherapy, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, # 3, Zhigong New Street, Xinghualing District, Taiyuan, Shanxi, 030013, People’s Republic of China, Email [email protected]: This study aims to evaluate the feasibility of using immune checkpoint-related gene polymorphisms and serum levels of PD-1, PD-L1 and CTLA4 in predicting chemotherapy resistance in patients with cervical cancer.Methods: Seven candidate SNPs in PDCD1, CD274 and CTLA4 were genotyped in 1032 cervical cancer patients (537 non-responders and 495 responders based on their responses to chemotherapy), and the serum level of PD-1, PD-L1 and CTLA4 was detected by ELISA.Results: The frequencies of minor allele A of PDCD1- rs2227982, CD274-rs2890658 and CTLA4-rs3087243 were significantly higher in non-responders than that in responders (p ≤ 0.0001). Moreover, the genotype AA of the three SNPs was associated with a 2.24, 3.78 and 2.71-fold increase in susceptibility to platinum resistance, respectively (p ≤ 0.0001). In addition, all of the three SNPs were associated with the risk of cisplatin resistance in both patients with squamous cell carcinoma and adenocarcinoma under different genetic models (p < 0.05). The serum concentrations of PD-L1 and CTLA4 in the non-responder group were significantly higher than those in the responder group (p < 0.0001). Moreover, the PD-L1 and CTLA4 levels of carriers with mutant genotypes of CD274-rs2890658 and CTLA4-rs3087243 were significantly higher than those of with wild-type, and the serum levels of homozygous mutant carriers were even higher (p < 0.0001).Conclusion: The PDCD1- rs2227982, CD274-rs2890658 and CTLA4- rs3087243 polymorphisms and high serum levels of PD-L1 and CTLA4 may predict chemotherapy resistance in cervical cancer patients.Keywords: platinum-based chemotherapy, chemotherapy resistance, cervical cancer, PD-L1, CTLA4