Merkel Cell Carcinoma: Integrating Epidemiology, Immunology, and Therapeutic Updates

Abstract

Merkel cell carcinoma (MCC) is a rare skin cancer characterized by neuroendocrine differentiation. Its carcinogenesis is based either on the integration of the Merkel cell polyomavirus or on ultraviolet (UV) mutagenesis, both of which lead to high immunogenicity either through the expression of viral proteins or neoantigens. Despite this immunogenicity resulting from viral or UV-associated carcinogenesis, it exhibits highly aggressive behavior. However, owing to the rarity of MCC and the lack of epidemiologic registries with detailed clinical data, there is some uncertainty regarding the spontaneous course of the disease. Historically, advanced MCC patients were treated with conventional cytotoxic chemotherapy yielding a median response duration of only 3 months. Starting in 2017, four programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) immune checkpoint inhibitors-avelumab, pembrolizumab, nivolumab (utilized in both neoadjuvant and adjuvant settings), and retifanlimab-have demonstrated efficacy in treating patients with disseminated MCC on the basis of prospective clinical trials. However, generating clinical evidence for rare cancers, such as MCC, is challenging owing to difficulties in conducting large-scale trials, resulting in small sample sizes and therefore lacking statistical power. Thus, to comprehensively understand the available clinical evidence on various immunotherapy approaches for MCC, we also delve into the epidemiology and immune biology of this cancer. Nevertheless, while randomized studies directly comparing immune checkpoint inhibitors and chemotherapy in MCC are lacking, immunotherapy shows response rates comparable to those previously reported with chemotherapy but with more enduring responses. Notably, adjuvant nivolumab has proven superiority to the standard-of-care therapy (observation) in the adjuvant setting.

Fig. 1.

Tumor antigen cross-presentation for priming of tumor-specific T cells. (1) Upon immunogenic cell death, damage-associated molecular patterns (DAMPs) are presented or released by the tumor cells. For example, dying cells will translocate calreticulin to the cell surface, release high-mobility group box 1 (HMGB1) protein, Annexin A1 (AXNA1) and adenosine triphosphate (ATP) and secrete type I interferons. (2) Immature dendritic cells (DCs) sense these DAMPs by pattern recognition receptors. This leads to maturation of the DCs and increased phagocytosis of released tumor antigens, which are subsequently processed and presented to T cells. (3) DCs migrate to the lymph node via the afferent lymphatic vessels. They might also migrate into tertiary lymphoid structures present at the tumor (in this case a peritumoral location is depicted). (4) In the lymph node and maybe also in TLS priming of T cells will take place. Depicted for cross priming of CD8+ T cells, full activation and clonal expansion of the T cells require three signals: (1) recognition of the MHC class I/peptide complex by the TCR, (2) costimulation of CD28 by B7 ligand, and (3) cytokines binding to cytokine receptor. (5) Primed T cells will leave the lymph node via efferent lymphatic vessel and are recruited to the tumor microenvironment where they can attack tumor cells expressing their cognate peptide

Fig. 2.

Antigenicity and immune escape in MCC. A On the basis of the different etiological factors leading to MCC development, VN-MCC should be able to present neoantigens while VP-MCC present TA-derived antigens. B Several immune escape mechanisms have been described for MCC. MDSC myeloid derived suppressor cell, N neutrophil, TAM tumor-associated macrophage, Treg regulatory T cell