Epidemiology, biology and therapy of Merkel cell carcinoma: conclusions from the EU project IMMOMEC

Abstract

Merkel cell carcinoma (MCC) is a highly aggressive, often lethal neuroendocrine cancer. Its carcinogenesis may be either caused by the clonal integration of the Merkel cell polyomavirus into the host genome or by UV-induced mutations. Notably, virally-encoded oncoproteins and UV-induced mutations affect comparable signaling pathways such as RB restriction of cell cycle progression or p53 inactivation. Despite its low incidence, MCC recently received much attention based on its exquisite immunogenicity and the resulting major success of immune modulating therapies. Here, we summarize current knowledge on epidemiology, biology and therapy of MCC as conclusion of the project 'Immune Modulating strategies for treatment of Merkel Cell Carcinoma', which was funded over a 5-year period by the European Commission to investigate innovative immunotherapies for MCC.

Keywords: Cell of origin; Epidemiology; IMMOMEC; Immunotherapy; Merkel cell carcinoma; Merkel cell polyomavirus.

Fig. 1

Domains and functions of MCPyV T antigens. a sT can (i) preserve 4E-BP1 hyperphosphorylation resulting in dysregulated cap-dependent translation [31], (ii) through inhibition of SCF Fbx7 ubiquitin ligase stabilize their cellular targets and MCPyV LT [32], (iii) interact with NEMO thereby inhibiting NF-κB-mediated transcription [–35], (iv) lead to a motile and migratory phenotype by promoting microtubule destabilization [36], (v) elevate aerobic glycolysis by regulating MCT-1 levels [37] and (vi) inactivate p53 pathway through recruitment of MAX and MYCL and binding to P400 complex resulting in increased expression of the p53 inhibitor MDM2. b In tumor cells, the C-terminal domains of LT containing several crucial elements required for viral replication are consistently truncated by tumor-associated mutations. The truncated LT can (i) mediate cell proliferation by binding RB1 [38], (ii) lead to gene expression alterations most of which require an intact RB binding site [39], (iii) disrupt lysosomal clustering by binding hVam6p and translocating it into the nucleus [40] and (iv) interact with Brd4 to RFC to the viral replication sites facilitating replication [41]. The latter two functions seem to be relevant for the normal life cycle of the virus. 4E-BP1 = eukaryotic translation initiation factor 4E-binding protein 1; SCF = the Skp1-Cul1-F-box protein; FBx7 = F-box protein 7; NEMO = NF-κB essential modulator; MCT-1 = monocarboxylat-Transporter 1; hVamp6 = human VAM-encoded protein; 6Brd4 = bromodomain protein 4; RFC = recruit replication factor C

Fig. 2

Immunogenicity of MCC. a MCCs can be divided upon their association with MCPyV. For both, viral and non-viral MCCs, the cell of origin has not yet been identified and, consequently, it is currently not known if they originate from the same cell. Although transformation is caused by the virus or by UV-induced mutations, they both lead to RB and p53 pathway inactivation. Immunogenicity of both tumors is high due to presentation of viral peptides or neoantigens, respectively [47]. b Based on programmed death-ligand 1 (PD-L1) expression and immune infiltrate, non-viral MCC cases can be divided into immune-resistant or immune-ignorant tumors. The latter demonstrate a lower mutagenic burden [47]. c MCC tumors present with a low/absent expression of the stress molecules MHC class I polypeptide-related sequence A and B (MICA/B). Treatment of MCC cells with histone deacetylases leads to induction/increased expression of MICA/B [8]. These natural killer group 2D (NKG2D) ligands act co-stimulatory on T cells and activate on NK cells. Consequently, the lysis of tumor cells by immune cells is increased after histone acetylase inhibition

Fig. 3

Blood-based biomarkers and immunotherapy. a Determination of antibody reactivity against sT in serum of MCC patients. Seropositivity at the time point of diagnosis is not only associated with a reduced risk of recurrence, but can be used diagnostically. To this end, a falling (< 20% to last sample) or negative titer has a negative predictive value of 97%, while rising titers (> 20%) has a positive predictive value of 66% for the occurrence of recurrence [57]. b Interfering with the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) signaling pathway by inhibitory antibodies achieve response rate of > 50% in the first line setting and about 30% in patients previously treated with chemotherapy [3, 4]