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Simple Summary: Despite the improvement in melanoma treatment over the last decade, there is still a need for developing new treatment strategies that can achieve complete and durable remission. Herein, we provide evidence that the kinase domain receptor (KDR) pathogenic germline variant Q472H confers more angiogenic and proliferative tumors, a more immune-suppressive microenvironment, and more resistance to therapy. Data suggest that anti-angiogenic therapy might be beneficial in patients harboring this genotype. Background: We previously reported a higher incidence of a pathogenic germline variant in the kinase insert domain receptor (KDR) in melanoma patients compared to the general population. Here, we dissect the impact of this genotype on melanoma tumor growth kinetics, tumor phenotype, and response to treatment with immune checkpoint inhibitors (ICIs) or targeted therapy. Methods: The KDR genotype was determined and the associations between the KDR Q472H variant (KDR-Var), angiogenesis, tumor immunophenotype, and response to MAPK inhibition or ICI treatment were examined. Melanoma B16 cell lines were transfected with KDR-Var or KDR wild type (KDR-WT), and the differences in tumor kinetics were evaluated. We also examined the impact of KDR-Var on the response of melanoma cells to a combination of VEGFR inhibition with MAPKi. Results: We identified the KDR-Var genotype in 81/489 (37%) patients, and it was associated with a more angiogenic (p = 0.003) and immune-suppressive tumor phenotype. KDR-Var was also associated with decreased PFS to MAPKi (p = 0.022) and a trend with worse PFS to anti-PD1 therapy (p = 0.06). KDR-Var B16 murine models had increased average tumor volume (p = 0.0027) and decreased CD45 tumor-infiltrating lymphocytes (p = 0.0282). The anti-VEGFR treatment Lenvatinib reduced the tumor size of KDR-Var murine tumors (p = 0.0159), and KDR-Var cells showed synergistic cytotoxicity to the combination of dabrafenib and lenvatinib. Conclusions: Our data demonstrate a role of germline KDR-Var in modulating melanoma behavior, including response to treatment. Our data also suggest that anti-angiogenic therapy might be beneficial in patients harboring this genotype, which needs to be tested in clinical trials. [ABSTRACT FROM AUTHOR]

Purpose: Immune checkpoint inhibition (ICI) shows benefits in adjuvant (AT) and neoadjuvant (NAT) melanoma treatments. However, ICI frequently induces severe immune-related adverse events (irAEs). Unlike metastatic disease, where irAEs are a clinical trade-off for treatment that improves survival, the toxicity burden from ICI in AT is a substantial clinical problem urging for irAE-predictive biomarkers., Experimental Design: We assessed post-surgical, pre-ICI treatment peripheral CD4+ and CD8+ T cells from clinical trial patients (CheckMate-915) treated with AT nivolumab (NIVO, n=130) or ipilimumab/nivolumab (COMBO, n=82). Performing RNA-seq differential gene expression analysis we tested baseline differences associated with severe (grade 3-5) irAEs and constructed an irAE-predictive model using LASSO-regularized logistic regression., Results: The analysis of predicted protein-protein interactions among differentially expressed genes (DEGs) in peripheral CD4+ cells revealed significant enrichment of the spleen tyrosine kinase (SYK) pathway, associated with severe irAEs in COMBO-treated patients. This gene-expression signature predicted severe-irAE COMBO patients (chi-square p-value=0.001) with 73% accuracy and was independent of disease recurrence (p=0.79). The irAE-predictive model incorporating this gene-expression signature demonstrated 82% accuracy (chi-square p-value=8.91E-06)., Conclusions: We identified baseline gene-expression differences in key immune pathways of peripheral blood T cells from COMBO-treated patients with grade 3-5 irAEs, and defined a SYK-related gene signature correctly identifying ~60% of COMBO-treated patients with grade 3-5 irAE. This finding aligns with our previous work linking anti-CTLA-4 irAEs with a germline variant associated with high SYK expression. This gene signature may serve as a baseline biomarker of severe grade 3-5 irAE risk, which is especially important in AT.

Background: We previously reported a higher incidence of a pathogenic germline variant in the kinase insert domain receptor (KDR) in melanoma patients compared to the general population. Here, we dissect the impact of this genotype on melanoma tumor growth kinetics, tumor phenotype, and response to treatment with immune checkpoint inhibitors (ICIs) or targeted therapy., Methods: The KDR genotype was determined and the associations between the KDR Q472H variant (KDR-Var), angiogenesis, tumor immunophenotype, and response to MAPK inhibition or ICI treatment were examined. Melanoma B16 cell lines were transfected with KDR-Var or KDR wild type (KDR-WT), and the differences in tumor kinetics were evaluated. We also examined the impact of KDR-Var on the response of melanoma cells to a combination of VEGFR inhibition with MAPKi., Results: We identified the KDR-Var genotype in 81/489 (37%) patients, and it was associated with a more angiogenic ( p = 0.003) and immune-suppressive tumor phenotype. KDR-Var was also associated with decreased PFS to MAPKi ( p = 0.022) and a trend with worse PFS to anti-PD1 therapy ( p = 0.06). KDR-Var B16 murine models had increased average tumor volume ( p = 0.0027) and decreased CD45 tumor-infiltrating lymphocytes ( p = 0.0282). The anti-VEGFR treatment Lenvatinib reduced the tumor size of KDR-Var murine tumors ( p = 0.0159), and KDR-Var cells showed synergistic cytotoxicity to the combination of dabrafenib and lenvatinib., Conclusions: Our data demonstrate a role of germline KDR-Var in modulating melanoma behavior, including response to treatment. Our data also suggest that anti-angiogenic therapy might be beneficial in patients harboring this genotype, which needs to be tested in clinical trials., Competing Interests: The authors declare no potential competing interests.