Understanding mechanisms of late/acquired cancer immunotherapy resistance is critical to improve outcomes; cellular immunotherapy trials offer a means to probe complex tumor-immune interfaces through defined T cell/antigen interactions.,We treated two patients with metastatic Merkel cell carcinoma with autologous Merkel cell polyomavirus specific CD8+ T cells and immune-checkpoint inhibitors.,In both cases, dramatic remissions were associated with dense infiltration of activated CD8+s into the regressing tumors.,However, late relapses developed at 22 and 18 months, respectively.,Here we report single cell RNA sequencing identified dynamic transcriptional suppression of the specific HLA genes presenting the targeted viral epitope in the resistant tumor as a consequence of intense CD8-mediated immunologic pressure; this is distinguished from genetic HLA-loss by its reversibility with drugs.,Transcriptional suppression of Class I loci may underlie resistance to other immunotherapies, including checkpoint inhibitors, and have implications for the design of improved immunotherapy treatments.,Acquired resistance is a major problem in cancer immunotherapy.,Here the authors report a study of two patients with Merkel cell carcinoma under immunotherapy treatment who develop resistance after deep responses for >1 year and identified a novel mechanism of acquired, gene-specific transcriptional suppression of HLAs.
Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy with poor prognosis.,Limited data exists to guide treatment decisions.,Here we report on our institutional experience and outcomes treating patients with MCC.,A database search (1984-2014) of patients treated at the University of Wisconsin Hospital and Clinics was used to identify patients with histologically confirmed MCC.,Patient, tumor, and treatment characteristics were examined via review of medical records.,Statistical analyses were performed to assess outcomes and associated prognostic factors.,A total of 87 patients with MCC were identified with a median follow-up of 17 months (mean: 38, range: 0-210 months).,Two and five-year overall survival rates were 53.9% and 32.8%, respectively.,Recurrence was documented in 31.0% of patients (85.2% locoregional, 48.1% distant and 33.3% both).,Patients with a history of immunosuppression exhibited significantly worse survival (hazard ratio, 2.01; 95% CI, 1.1-3.7) when compared to immune-competent individuals.,The head and neck region was the most common location of primary lesion (N=49) followed by the extremities (N=31).,Upper extremity primaries predicted significantly better overall survival (hazard ratio, 0.48; 95% CI, 0.23-0.99) while lower extremity primaries did not have significantly better results (hazard ratio, 0.5; 95% CI, 0.21-1.2) in comparison to head and neck site of primary.,Nodal involvement (hazard ratio, 2.95; 95% CI, 1.5-5.79) was also a negative prognostic factor associated with poor overall survival when compared with clinically node negative patients.,Primary tumor size > 2 cm (hazard ratio, 1.76; 95% CI, 0.91-3.4) was not associated with survival.,This study highlights the role of various factors in determining prognosis of Merkel cell carcinoma; history of immunosuppression, nodal involvement, and head/neck primary predicted worse overall survival.,These findings suggest that improvements in both distant and locoregionally directed therapies might play an important role in control of MCC and identify areas for future study.