Background Melanoma has high response rate to immune checkpoint inhibitors. KIT, a driver mutation in melanoma seen in ~10% of the patients.1 However, the role of the KIT mutation in immune microenvironment of melanoma is not well established yet. Here we report a case with KIT mutation and a likely impaired B cell activity with poor response to Immune-checkpoint inhibitor therapy (ICI). We also describe the overall survival of melanoma depending on KIT mutation and MS4A1/CD20 expression, which encodes CD20, B-lymphocyte-specific membrane protein that plays a role in the development, differentiation, and activation of B-lymphocytes.2
Methods A case with poor response to ICI with KIT mutation and monoclonal B cell lymphocytosis was identified. Clinical and molecular characteristics of melanoma in TCGA was analyzed using cBioPortal web page. TCGA data were analyzed to determine KIT mutation status and MS4A1/CD20 expression in melanoma cohort. Samples in the upper 33 percentile of MS4A1 expression were identified as high expression, and the lower 33 percentile were identified as low expression. Mantel-Cox method was used for overall survival (OS) comparison between the cohorts.
Results 69-year-old male with initial diagnosis of stage III-B melanoma of the left thumb with local recurrence in the resection site and then lung metastases. Patient was then started on nivolumab/ipilimumab with rapid progression on immunotherapy. He was found to have KIT mutation (exon 13K642EMT), and started on imatinib, but he continued to have progression. He was switched to temozolomide with no response. He also had history of leukopenia, pre-dating the metastatic melanoma and was diagnosed with monoclonal B cell lymphocytosis. With the hypothesis that the patient‘s dysfunctional B cells may have impaired ability of ICI and poor prognosis; we analyzed TCGA database for KIT mutation and MS4A1/CD20 expression- which was used as marker for B cell activity. KIT mutation was seen in 10 of 147 patients with high MS4A1/CD20 expression, and 10 of 135 patients with low MS4A1/CD20 expression. Overall survival was 15 months for the patients with KIT mutation and low MS4A1/CD20 expression, and significantly lower when compared with other groups despite low number of patients. (P<0.0001) (figure 1).
Conclusions B cells have significant role in immune response to tumor. Lower expression of MS4A1/CD20 is known to be associated with poor prognosis in melanoma and other solid tumors.3 We demonstrated that a concurrent KIT mutation in melanoma with lower expression of MS4A1/CD20 contributes to poor prognosis in melanoma. Therefore, this small subset of aggressive tumors may need combination strategies involving targeting driver pathways with a kinase and immune checkpoint inhibitor.
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Liu Y, Wang L, Lo KW, Lui VW. Omics-wide quantitative B-cell infiltration analyses identify GPR18 for human cancer prognosis with superiority over CD20. Communications biology 2020 May 12;3(1):1–1.
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