Germline polymorphism of interferon-lambda3 is clinically associated with progression of renal cell carcinoma
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Akinori Nukui1,*, Yoshiaki Yanai2, Toyonori Tsuzuki3, Hideyuki Abe1, Kyoko Arai1, Ken-Ichiro Yoshida1 and Takao Kamai1,*
1Department of Urology, Dokkyo Medical University, Mibu, Tochigi, Japan
2Pharmaceutical Marketing Division, Otsuka Pharmaceutical Co. Ltd, Tokushima, Japan
3Department of Surgical Pathology, Aichi Medical University, Nagakute, Japan
*These authors contributed equally to this work
Takao Kamai, email: firstname.lastname@example.org
Keywords: IFN-lambda3; IL-28B; polymorphism; PD-L1; Akt
Received: March 17, 2017 Accepted: December 20, 2017 Published: December 25, 2017
Renal cell carcinoma (RCC) is an immunogenic tumor that shows a metabolic shift to aerobic glycolysis. The immune system can have opposing host-protective and tumor-promoting effects, and aerobic glycolysis suppresses antitumor immunity. In addition to immunostimulatory effect, increasing numbers of studies have revealed that interferon (IFN) is also involved in promoting immunosuppression. Since various single nucleotide polymorphisms (SNPs) can influence the outcome of anticancer therapy, we investigated SNPs for IFN-lambda3, a new member of IFN family, in 53 patients with metastatic RCC who underwent cytoreductive nephrectomy. The 16 patients who were heterozygous/homozygous for the minor alleles of SNPs for IFN-lambda3 had a significantly worse response to sequential vascular endothelial growth factor-targeting therapy (P = 0.0029) and shorter survival (P = 0.0033) compared with the 37 patients possessing the major alleles of SNPs for IFN-lambda3. In these 16 patients, the primary tumor showed elevated glucose uptake on positron emission tomography with [18F] fluorodeoxyglucose (P = 0.0160) and increased expression of programmed cell death 1 (PD-1)-ligand 1 (PD-L1) and phosphorylated serine/threonine kinase Akt (P = 0.0006 and P = 0.0043, respectively) compared to the tumors of the patients without these alleles. Since IFN-induced PD-L1 expression on either tumor cells or tumor-infiltrating mononuclear cells can trigger immunosuppression due to crosstalk between cancer cells and T cells, IFN-lambda3 polymorphism might be linked to the immunosuppressive effects of IFNs in cancer. Although this retrospective study lacks mechanistic insight, our findings suggest that IFN-lambda3 polymorphism might be relevant to the progression of RCC.
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