267P Vaccine-induced PD-L1-specific T cells indirectly enhance antitumor immunity through myeloid cell modulation

Background:The immune modulatory vaccine (IMV) targeting IDO and PD-L1 is designed to enhance T cell responses against both cancer cells and immunosuppressive populations in the tumor microenvironment (TME).When combined with anti-PD-1 therapy, it showed clinical activity in patients with advanced metastatic melanoma in a phase I/II trial 1 .Here we investigate how vaccine-activated T cells modulate target-expressing cancer and immune cells and contribute to tumor elimination.1. Kjeldsen, J. W. et al.A phase 1/2 trial of an immune-modulatory vaccine against IDO/PD-L1 in combination with nivolumab in metastatic melanoma.Nat Med 27, 2212Med 27, -2223Med 27, (2021)).Methods: PD-L1-specific CD4 + T cell clones expanded from peripheral blood mononuclear cells (PBMCs) of vaccinated patients from the phase I/II trial were cocultured with autologous cancer cells and PBMC-derived CD14 + myeloid cells.T cell reactivity toward cancer and CD14 + cells was assessed using IFN- ELISPOT.Phenotypic profiles of myeloid cells were analyzed with flow cytometry, and cancer cell killing was assessed using xCELLigence system, in the presence and absence of autologous tumor-infiltrating lymphocytes (TILs).Results: Vaccine-induced PD-L1-specific CD4 + T cells showed reactivity against PD-L1 + myeloid cells co-cultured with PD-L1 + cancer cells in ELISPOT assays.Phenotypic analysis of myeloid cells revealed a shift toward an immunosuppressive profile induced by cancer cells, which was reversed by the addition of PD-L1-specific CD4 + T cells.In xCELLigence assays, targeting of CD14 + cells by PD-L1-specific CD4 + T cells promoted cancer cell killing and simultaneously enhanced the cytotoxic activity of tumor-reactive TILs. Conclusions:Our data demonstrate that vaccine-activated PD-L1-specific T cells can directly target and reprogram PD-L1 + myeloid cells, leading to cancer cell elimination both through myeloid cell modulation and by improving TIL cytotoxicity.These results highlight the potential of IMVs to promote an immunopermissive TME by reprogramming immunosuppressive myeloid cells, supporting their combination with checkpoint therapies.