Epigenetic priming restores the HLA class-I antigen processing machinery expression in Merkel cell carcinoma

Abstract

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.

Characterization of six Merkel cell polyomavirus‐positive Merkel cell carcinoma cell lines: Integration pattern suggest that large T antigen truncating events occur before or during integration

“…To this end, WaGa, which is very frequently used due to its short doubling time and its growth as suspension cell line, demonstrated 100% tumorgenicity. This has been utilized already in several published studies . Also for BroLi, two attempts of tumor induction in NOD/SCID mice were successful, while in case of LoKe and WoWe we observed sometimes failure of tumor formation.…”

Merkel cell carcinoma

“…Consequently, an understanding of these immune escape mechanisms is necessary to overcome these issues. MCC cells might lack expression of classical and non-classical major histocompatibility complex (MHC) molecules, a phenotype that can impair both adaptive and innate immune responses 71,148–150 . The downregulation of MHC class I molecules can be reversed either by therapy with class I interferons or by epigenetic modifications.…”

“…Moreover, infiltrating T cells are often characterized by an exhausted phenotype 68,69 (a process in which T cells progressively lose their function) 70 . Lack of T cell infiltration could reflect different immune escape strategies of MCC cells, such as inhibition of cellular immune responses via programmed cell death protein 1 (PD1) and PD1 ligand 1 (PDL1) signalling or defects in human leukocyte antigen (HLA) class I expression 71 . Decreases in HLA class I antigens on the cell surface can also partially explain primary or secondary resistance of MCC to PD1–PDL1 blockade therapy, which relies on restoring adaptive T cell responses that, in turn, crucially depend on HLA class I-restricted antigen presentation 72 .…”

Generation of Tumor-Reactive T Cells by Co-culture of Peripheral Blood Lymphocytes and Tumor Organoids

“…Despite these encouraging results, a large fraction of patients does not respond to current immunotherapies. Treatment failure may be explained at many different levels that include a low number of immunogenic antigens, defective antigen presentation, and/or the expression of alternative immune checkpoint molecules (Blank et al, 2016; Dijkstra et al, 2016; Pitt et al, 2017; Sharma et al, 2017). Given the large variety in mechanisms of immune evasion by cancers, it is presently challenging to predict whether an individual patient will be sensitive to immunotherapy, what mechanism is likely to underlie resistance and what alternative treatment could potentially overcome such resistance.…”