BackgroundAn anti-programmed cell death protein 1 monoclonal antibody, nivolumab, is one of the most effective drugs for advanced melanoma. Tumor cell-derived or immune cell-derived markers and clinical predictors such as serum lactate dehydrogenase (LDH) and cutaneous adverse events, have already been described as prognostic factors for advanced melanoma treated with nivolumab. We sought to identify further clinical predictors that can be determined in routine clinical practice.MethodsWe retrospectively analyzed clinical findings of 98 consecutive patients with unresectable stage III or IV melanoma treated with nivolumab, at the National Cancer Center Hospital or at Keio University Hospital, in Tokyo, Japan, between July 2014 and July 2016. These patients had been administered nivolumab at a dose of 2mg/kg every 3 weeks.ResultsAs for pretreatment prognostic factors, ECOG performance status (PS) ≥1, maximum tumor diameters of ≥30mm, elevated LDH and elevated C-reactive protein were significantly associated with poor overall survival (OS) (hazard ratio [HR] 0.29 [P<0.001], HR 0.40 [p=0.003], HR 0.29 [P<0.001], HR 0.42 [P=0.004], respectively) on univariate analysis. Among these factors, PS and LDH were identified as independent variables by multivariate analysis. As for early markers examined during therapy, patients with absolute lymphocyte count (ALC) ≥ 1000/μl (Week3: HR 0.40 [P=0.004], Week6: HR 0.33 [P=0.001]) and absolute neutrophil count (ANC) <4000/μl (Week3: HR 0.46 [P=0.014], Week6: HR 0.51 [P=0.046]) had significantly better OS.ConclusionALC≥1000/μl and ANC<4000/μl during treatment appear to be early markers associated with OS. Nivolumab might have minimal efficacy in patients with a massive tumor burden.

The significance of Hedgehog (HH) signaling in the development of basal cell carcinoma (BCC) has been established. Although several target genes of HH signaling have been described previously, their precise role in tumorigenesis and cell proliferation is not yet known. To identify genes responsible for tumor formation in BCC, we screened a DNA microarray database of human BCC cases; the orphan G-protein-coupled receptor GPR49 was found to be up-regulated in all cases. GPR49 is a novel gene reported to be a marker of follicular and other tissue stem cells. Using real-time quantitative RT-PCR analysis, significant expression of GPR49 mRNA was observed in 19 of 20 BCC cases (95%) compared with controls. Up-regulation of GPR49 was confirmed by in situ hybridization. Moreover, knockdown of mouse Gpr49 showed suppression of cell proliferation in a mouse BCC cell line, and overexpression of GPR49 in human immortalized keratinocyte HaCaT cells induced proliferation. Furthermore, HaCaT cells overexpressing GPR49 showed tumor formation when transplanted into immunodeficient mice. In addition, inhibition of the HH signaling pathway in a mouse BCC cell line down-regulated endogenous Gpr49, whereas activation of HH signaling in mouse NIH3T3 cells up-regulated endogenous GPR49. These results suggest that GPR49 is expressed downstream of HH signaling and promotes cell proliferation and tumor formation in cases of BCC.

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While melanoma is believed to be a highly immunogenic tumor and recent developments in immunotherapies are promising. Interferon-γ (IFN-γ) produced by immune cells plays a crucial role in tumor immune surveillance; however, it has also been reported to be pro-tumorigenic. In the current study, we found that IFN-γ enhances the expression of CD74, which interacts with its ligand, macrophage migration inhibitory factor (MIF), and thereby activates the PI3K/AKT pathway in melanoma, promoting tumor survival. IFN-γ increased phosphorylation of AKT Ser473 and upregulated total and cell surface expression of CD74 in human melanoma cell lines tested. CD74 was highly expressed in melanoma tissues. Moreover, the expression of CD74 on tumor cells correlated with plasma IFN-γ levels in melanoma patient samples. In our analysis of melanoma cell lines, all produced MIF constitutively. Blockade of CD74-MIF interaction reduced AKT phosphorylation and expression of pro-tumorigenic molecules, including interleukin-6, interleukin-8 and BCL-2. Inhibition of CD74-MIF interaction significantly suppressed tumor growth in the presence of IFN-γ in our xenograft mouse model. Thus, we conclude that IFN-γ promotes melanoma cell survival by regulating CD74-MIF signaling, suggesting that targeting the CD74-MIF interaction under IFN-γ–stimulatory conditions would be an effective therapeutic approach for melanoma.