Abstract
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.
Highlights
Increased angiogenesis and evasion of the host immune system are two mechanisms assisting the proliferation and metastasis of renal cell carcinoma (RCC), and this cancer displays impairment of oxidative phosphorylation with a metabolic shift to aerobic glycolysis (Warburg effect) [1]
IFN-lambda3 polymorphism was not correlated with the Fuhrman grade, local invasion, regional lymph node involvement, or metastatic site of clear cell Renal cell carcinoma (RCC) (Table 2 and Supplementary Table 1)
The present retrospective study identified several differences between patients who were heterozygous/ homozygous for the minor alleles of IFN-lambda3 single nucleotide polymorphisms (SNPs) and patients who were homozygous for the major alleles, with the heterozygous/homozygous the minor alleles patients showing 1) an unfavorable response to sequential vascular endothelial growth factor (VEGF)-targeting therapy, 2) a worse prognosis, 3) elevation of SUVmax in the primary tumor, and 4) increased expression of pAkt(Ser-473) and progressive disease (PD)-L1 in the primary tumor
Summary
Increased angiogenesis and evasion of the host immune system are two mechanisms assisting the proliferation and metastasis of renal cell carcinoma (RCC), and this cancer displays impairment of oxidative phosphorylation with a metabolic shift to aerobic glycolysis (Warburg effect) [1]. It is currently accepted that the immune system can have both host-protective and tumor-promoting actions [4,5,6]. There is growing evidence that host antitumor mechanisms are induced by local production of IFNs [7,8,9,10]. IFN-alpha promotes the activation of T cells and dendritic cells, as well as antiangiogenic activity including the inhibition of vascular endothelial growth factor (VEGF), which may lead to IFN-induced antitumor immunity. Some patients with metastatic RCC showed a durable antitumor response to IFN-alpha, the number is small [11]. Type III IFNs have antitumor effects [12]
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