Based on its viral-associated or UV-associated carcinogenesis, Merkel cell carcinoma (MCC) is a highly immunogenic skin cancer.,Thus, clinically evident MCC occurs either in immuno-compromised patients or based on tumor-intrinsic immune escape mechanisms.,This notion may explain that although advanced MCC can be effectively restrained by treatment with PD-1/PD-L1 immune checkpoint inhibitors (ICIs), a considerable percentage of patients does not benefit from ICI therapy.,Biomarkers predicting ICI treatment response are currently not available.,The present multicenter retrospective study investigated clinical and molecular characteristics in 114 patients with unresectable MCC at baseline before treatment with ICI for their association with therapy response (best overall response, BOR).,In a subset of 21 patients, pretreatment tumor tissue was analyzed for activation, differentiation and spatial distribution of tumor infiltrating lymphocytes (TIL).,Of the 114 patients, n=74 (65%) achieved disease control (BOR=complete response/partial response/stable disease) on ICI.,A Bayesian cumulative ordinal regression model revealed absence of immunosuppression and a limited number of tumor-involved organ systems was highly associated with a favorable therapy response.,Unimpaired overall performance status, high age, normal serum lactate dehydrogenase and normal serum C reactive protein were moderately associated with disease control.,While neither tumor Merkel cell polyomavirus nor tumor PD-L1 status showed a correlation with therapy response, treatment with anti-PD-1 antibodies was associated with a higher probability of disease control than treatment with anti-PD-L1 antibodies.,Multiplexed immunohistochemistry demonstrated the predominance of CD8+ effector and central memory T cells (TCM) in close proximity to tumor cells in patients with a favorable therapy response.,Our findings indicate the absence of immunosuppression, a limited number of tumor-affected organs, and a predominance of CD8+ TCM among TIL, as baseline parameters associated with a favorable response to PD-1/PD-L1 ICI therapy of advanced MCC.,These factors should be considered when making treatment decisions in MCC patients.
Merkel cell carcinoma (MCC) is a rare and aggressive, yet highly immunogenic skin cancer.,The latter is due to its viral or UV-associated carcinogenesis.,For tumor progression MCC has to escape the host’s immuno-surveillance, e.g. by loss of HLA class-I expression.,Indeed, a reduced HLA class-I expression was observed in MCC tumor tissues and MCC cell lines.,This reduced HLA class-I surface expression is caused by an impaired expression of key components of the antigen processing machinery (APM), including LMP2 and LMP7 as well as TAP1 and TAP2.,Notably, experimental provisions of HLA class-I binding peptides restored HLA class-I surface expression on MCC cells.,Silencing of the HLA class-I APM is due to histone deacetylation as inhibition of histone deacetylases (HDACs) not only induced acetylation of histones in the respective promoter regions but also re-expression of APM components.,Thus, HDAC inhibition restored HLA class-I surface expression in vitro and in a mouse xenotransplantation model.,In contrast to re-induction of HLA class-I by interferons, HDAC inhibitors did not interfere with the expression of immuno-dominant viral proteins.,In summary, restoration of HLA class-I expression on MCC cells by epigenetic priming is an attractive approach to enhance therapies boosting adaptive immune responses.