T antigen-specific CD8+ T cells associate with PD-1 blockade response in virus-positive Merkel cell carcinoma
Ulla Kring Hansen1,2, Candice D Church3, Ana Micaela Carnaz Simões2
1Section of Experimental and Translational Immunology, Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark.
Abstract:
Merkel cell carcinoma (MCC) is a highly immunogenic skin cancer primarily induced by Merkel cell polyomavirus, which is driven by the expression of the oncogenic T antigens (T-Ags). Blockade of the programmed cell death protein-1 (PD-1) pathway has shown remarkable response rates, but evidence for therapy-associated T-Ag-specific immune response and therapeutic strategies for the nonresponding fraction are both limited. We tracked T-Ag-reactive CD8+ T cells in peripheral blood of 26 MCC patients under anti-PD1 therapy, using DNA-barcoded pMHC multimers, displaying all peptides from the predicted HLA ligandome of the oncoproteins, covering 33 class I haplotypes. We observed a broad T cell recognition of T-Ags, including identification of 20 T-Ag-derived epitopes we believe to be novel. Broadening of the T-Ag recognition profile and increased T cell frequencies during therapy were strongly associated with clinical response and prolonged progression-free survival. T-Ag-specific T cells could be further boosted and expanded directly from peripheral blood using artificial antigen-presenting scaffolds, even in patients with no detectable T-Ag-specific T cells. These T cells provided strong tumor-rejection capacity while retaining a favorable phenotype for adoptive cell transfer. These findings demonstrate that T-Ag-specific T cells are associated with the clinical outcome to PD-1 blockade and that Ag-presenting scaffolds can be used to boost such responses.
Insights
Merkel cell carcinoma (MCC) patients responding to PD-1 blockade therapy show increased T-antigen specific T cells. Artificial antigen-presenting scaffolds can boost these T cells for potential adoptive cell transfer and improved outcomes.
Area of Science:
- Immunology
- Oncology
- Virology
Background:
- Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer linked to Merkel cell polyomavirus (MCPyV).
- Anti-PD-1 therapy shows promise in MCC, but understanding the associated T-cell response and improving outcomes for non-responders remains crucial.
- Oncogenic T antigens (T-Ags) from MCPyV are key drivers of MCC and potential targets for immunotherapy.
Purpose of the Study:
- To investigate the T-antigen (T-Ag)-specific CD8+ T cell response during anti-PD-1 therapy in MCC patients.
- To identify novel T-Ag epitopes and assess their association with clinical response and progression-free survival.
- To explore the potential of artificial antigen-presenting scaffolds for expanding T-Ag-specific T cells for therapeutic use.
Main Methods:
- Tracking T-Ag-reactive CD8+ T cells in 26 MCC patients undergoing anti-PD-1 therapy using DNA-barcoded pMHC multimers.
- Analysis of T-cell recognition across 33 class I HLA haplotypes, covering the predicted HLA ligandome of MCPyV T-Ags.
- In vitro expansion and functional assessment of T-Ag-specific T cells using artificial antigen-presenting scaffolds.
Main Results:
- Broad T cell recognition of T-Ags was observed, with the identification of 20 potentially novel T-Ag-derived epitopes.
- An increased frequency and broadened recognition profile of T-Ag-specific T cells correlated strongly with clinical response and prolonged progression-free survival.
- Artificial antigen-presenting scaffolds successfully boosted and expanded T-Ag-specific T cells, even from patients with initially undetectable responses, demonstrating tumor-rejection capacity.
Conclusions:
- T-antigen-specific T cell responses are associated with clinical outcomes in MCC patients treated with PD-1 blockade.
- Artificial antigen-presenting scaffolds represent a viable strategy to enhance T-Ag-specific T cell immunity for MCC treatment.
- Targeting T-Ag-specific T cells holds promise for improving therapeutic strategies in Merkel cell carcinoma.
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