Immune evasion mechanisms and immune checkpoint inhibition in advanced merkel cell carcinoma

Abstract

Merkel cell carcinoma (MCC) is a rare skin cancer caused by Merkel cell polyomavirus (MCPyV) infection and/or ultraviolet radiation-induced somatic mutations. The presence of tumor-infiltrating lymphocytes is evidence that an active immune response to MCPyV and tumor-associated neoantigens occurs in some patients. However, inhibitory immune molecules, including programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1), within the MCC tumor microenvironment aid in tumor evasion of T-cell-mediated clearance. Unlike chemotherapy, treatment with anti-PD-L1 (avelumab) or anti-PD-1 (pembrolizumab) antibodies leads to durable responses in MCC, in both virus-positive and virus-negative tumors. As many tumors are established through the evasion of infiltrating immune-cell clearance, the lessons learned in MCC may be broadly relevant to many cancers.

Keywords: Avelumab; Merkel cell carcinoma; PD-1; PD-L1; checkpoint inhibition; immune evasion; pembrolizumab.

Figure 1.

Mechanisms of MCPyV and UV exposure–induced tumorigenesis. Tumorigenesis is a multistep process, and in MCC, this occurs as a result of viral infection of cells within the epithelium or chronic UV radiation exposure of the skin, or both. (C, cytosine; DC, dendritic cell; IFN, interferon; IL, interleukin; LT, large T antigen; MΦ, macrophage; sT, small T antigen; T, thymine; TNF, tumor necrosis factor).

Figure 2.

MCC immune evasion strategies. MCC tumors may be targeted by the immune system for eradication. This process may be thwarted by several mechanisms, including 1) inhibition of T-cell migration into areas of inflammation by interrupting interactions between T-cell surface receptors and the tumor endothelium; 2) by alterations in gene expression that reduce the surface expression of MICA/MICB and MHC, molecules that are necessary for NK and T-cell–mediated cytolysis of tumor cells; 3) upregulation of inhibitory receptors on effector immune cells in the tumor microenvironment; 4) effector CD8⁺ T cells that have migrated to the tumor site can be inactivated by receptors present on the surface of tumor cells, particularly PD-L1; and 5) the recruitment of Tregs to areas of inflammation, which can suppress immune responses. (APC; antigen-presenting cell; B2M, β2-microglobulin; C/EBP, CCAAT/enhancer-binding protein; CLA, cutaneous lymphocyte antigen; CTLA-4, cytotoxic T-lymphocyte-associated protein 4); IFN, interferon; IL, interleukin; LAG-3, lymphocyte-activation gene 3; MHC, major histocompatibility complex; MICA, MHC class I chain-related protein A; MICB, MHC class I chain-related protein B; MΦ, macrophage; NK, natural killer; NKG2D, natural killer group 2D; PD-1, programmed death-1; PD-L1, programmed death-ligand 1; TCR, T-cell receptor; TIM-3, T-cell immunoglobulin and mucin-domain containing-3; TLR, Toll-like receptor; TGF, tumor growth factor).