Human CD4+ T Cells Specific for Merkel Cell Polyomavirus Localize to Merkel Cell Carcinomas and Target a Required Oncogenic Domain

Abstract

Although CD4 + T cells likely play key roles in antitumor immune responses, most immunooncology studies have been limited to CD8 + T-cell responses due to multiple technical barriers and a lack of shared antigens across patients. Merkel cell carcinoma (MCC) is an aggressive skin cancer caused by Merkel cell polyomavirus (MCPyV) oncoproteins in 80% of cases. Because MCPyV oncoproteins are shared across most patients with MCC, it is unusually feasible to identify, characterize, and potentially augment tumor-specific CD4 + T cells. Here, we report the identification of CD4 + T-cell responses against six MCPyV epitopes, one of which included a conserved, essential viral oncogenic domain that binds/disables the cellular retinoblastoma (Rb) tumor suppressor. We found that this epitope (WED LT209-228 ) could be presented by three population-prevalent HLA class II alleles, making it a relevant target in 64% of virus-positive

Robust Production of Merkel Cell Polyomavirus Oncogene Specific T Cells From Healthy Donors for Adoptive Transfer

“…Clinical trials have demonstrated that ACT and tumor infiltration by Th1 CD4 + T cells can mediate regression of advanced solid tumors (36)(37)(38)(39)(40). Recently it was shown that MCPyV TAg-specific CD4 + T cells are enriched in VP-MCC tumors (20), demonstrating that MCPyV MHC class II restricted TAg epitopes are relevant to tumor immunity. Th1 CD4 + cells engage in canonical activation and recruitment of innate immune cells and CD8 + cells to direct anti-tumor immunity (41,42).…”

“…Electroporated APCs and several rounds of stimulation produced MCPyV TAg-specific CD8 + T cells from healthy donors (50). However, several studies using HLA class I tetramers and multimers also failed to isolate CD8 + MCPyV TAg restricted epitopes from healthy donors, suggesting CD8 + TAg specific T cells may be low frequency in the healthy donor T cell repertoire (12,(18)(19)(20).…”

“…ACT with peptide library-pulsed ex vivo expanded virus or tumor antigen-specific T cells has been used with success in multiple clinical trials to treat viral infections, EBV-driven lymphomas, and solid tumors (15)(16)(17). MCPyV TAg specific CD4 + , but not CD8 + , T cells have been found in healthy donors and have not been evaluated for ACT (12,(18)(19)(20). Here, we show that polyclonal MCPyV TAg specific CD4 + T cells appropriate for ACT treatment of patients with VP-MCC can be generated in vitro from healthy donors using methods easily adaptable to clinical grade manufacture.…”

Merkel Cell Carcinoma: New Trends

“…T-cell responses to these antigens are reported [ 89 ], which might explain the rare cases of spontaneous regression [ 33 , 90 ] but in the vast majority of cases, this immune response is suboptimal and ineffective for various reasons. It has been suggested to enhance this immune response by therapeutic vaccination to T-antigen under the assumption that the “nonself” viral antigen can trigger a stronger and more tumor-specific response compared to less cancer specific overexpressed oncoproteins [ 91 , 92 ]. Therapeutic MCPyV vaccination has been explored in a murine melanoma tumor line [ 93 ].…”

From Merkel Cell Polyomavirus Infection to Merkel Cell Carcinoma Oncogenesis

“…Most pressingly, methods of limiting MCPyV infection and thereby preventing MCC onset have yet to be discovered. In recent years, however, efforts have been aimed at exploiting the presence of MCPyV oncoproteins in MCCs to develop targeted therapies for virus-positive MCC tumors (Chapuis et al, 2014 ; Gavvovidis et al, 2018 ; Longino et al, 2019 ; Sarma et al, 2020 ). The potential for expanding on these opportunities to provide prophylactic or therapeutic interventions for a highly lethal skin cancer should not be overlooked.…”