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Background Activation of the Transforming Growth Factor (TGF)-β signaling cascade plays an essential role in a wide range of tumors and other diseases. Indeed, cancer cells and components of the tumor microenvironment ( e.g. fibroblasts, immune cells, and blood vessels) exploit this pathway to support disease progression during tumor evolution. Nonetheless, global inhibition strategies targeting the TGF-β pathway in clinical studies thus far fell short of the anticipated success. Herein, we report an alternative approach, where TGF-β-specific T cells are activated through a peptide vaccination to target TGF-β-expressing cells to promote anti-tumor activities. This strategy is supported by earlier studies reporting the existence of intrinsic T cell immunity against TGF-β in man.1 2 Methods We employed human peripheral blood mononuclear cells (PBMCs) to measure T cell reactivity towards candidate TGF-β-derived peptides using an in vitro interferon (IFN)-γ ELISpot. The functional phenotype of such reactive T cells was characterized by flow cytometry analysis. In parallel, anti-tumor activity of TGF-β peptide vaccination was assessed in a mouse model of prostate cancer generated through in vivo CRISPR/Cas9 genome editing of 6 individual genes, as previously described.3 The effect of the vaccination was evaluated using ex vivo IFN-γ ELISpot, spatial analysis and scoring of micro and macro metastasis in the lungs.Results We confirmed that TGF-β encompasses immunogenic peptide sequences that elicit T cell responses in the human peripheral blood in line with previous findings. 1 2 Upon in vitro stimulation, the TGF-β-specific T cells further showed upregulation of T cell functional markers.TGF-β vaccination in the CRISPR/Cas9-driven murine model of prostate cancer led to the reduction of the total tumor burden, without affecting the overall welfare of the animals. Ex vivo IFN-γ responses confirmed the expansion and activation of TGF-β-specific T cells upon immunization. Moreover, spatial analysis revealed that the TGF-β vaccine decreased the proportion of tumor regions dominated by immunosuppressive macrophages, while it increased those where tumor cells and cytotoxic lymphocytes coexist, thereby suggesting an anti-tumorigenic response. Finally, the metastatic dissemination to the lungs was reduced by 35% compared to control mice.Conclusions Our data indicated the activity of TGF-β peptide vaccine in eliciting an immune response in both human ( in vitro) and mouse (in vivo) which could inhibit tumor growth and reduced lung metastasis in a murine model of cancer. These observations warrant further preclinical investigation to better understand the activity and the safety profile of this novel TGFβ-targeting strategy.References Holmström, et al. 2021; DOI: 10.1038/s41423-020-00593-5Mortensen, et al. 2021; DOI: 10.1038/s41423-021-00770-0Cai, et al. 2024; DOI: 10.1038/s41467-024-46370-0