Abstract B117: A TGF-β-directed peptide vaccine induces T cell activation and drives antitumor activity by modulating the architecture of the tumor microenvironment

Abstract Activation of the Transforming Growth Factor (TGF)-β signaling cascade plays an essential role in broad tumor types and other disease settings. While activation of TGF-β is tightly controlled in physiological conditions, cancer cells and components of the tumor microenvironment (e.g. fibroblasts, myeloid cells, and blood vessels) exploit this pathway to support disease progression during tumor evolution. Nonetheless, global inhibition strategies in clinical studies thus far fell short of the anticipated success mainly due to systemic toxicity, as such reinforcing the essential role of the different isoforms of this pleiotropic cytokine. These clinical observations suggest that TGF-β modulation –rather than its inhibition— could be the key in sustaining meaningful antitumoral activity in the clinical setting. We report here an alternative approach, where TGF-β-expressing cells are targeted via a peptide vaccine directed against TGF-β-specific T cell epitopes. This is based on earlier studies reporting the existence of intrinsic T cell immunity against TGF-β in human (Halmström et al., 2021; Mortensen et al., 2021), thus supporting the rationale for targeting these T cells through a vaccine encoding TGF-β epitopes. In order to assess this approach, we employed a range of murine platforms that were validated for TGF-β expression by means of DAB-IHC, including the syngeneic Pan02 cell-based model of pancreatic adenocarcinoma (PDAC) as well as a CRISPR/Cas9-driven model of prostate cancer (Cai et al., 2024). Collectively, treatment with the TGF-β vaccine significantly reduced the total tumor burden in both mouse models, without affecting the body weight and overall welfare of the animals. Moreover, ex vivo T-cell responses were evaluated through interferon (IFN)-g ELISpot, which confirmed expansion and activation of TGF-β-specific T cells upon immunization. Compared to overt malignant masses in the control cohort, TGFβ-directed immunization slowed down the progression of prostate tumors in the CRISPR/Cas9 model, as evinced by the numerous premalignant-like hyperplastic glands and resembling more physiological structures. Furthermore, smooth muscle actin (α-SMA) staining in the Pan02 model uncovered that the treatment ameliorated the fibrotic response –a hallmark of PDAC in the clinical setting– in this experimental setup, with an increased infiltration of CD8+ lymphocytes and F4/80+ macrophages into the TME. Currently, in order to clarify the mechanism of action, we are implementing in vivo models of metastatic disease and exploring spatial relationships to identify which cell types and tissue architectures are pivotal for meaningful responses. In conclusion, our data warrant further preclinical interrogation to better understand the efficacy and the safety profile of this novel TGFβ-targeting strategy. References: - Holmström et al., 2021; DOI: 10.1038/s41423-020-00593-5 - Mortensen et al., 2021; DOI: 10.1038/s41423-021-00770-0 - Cai et al., 2024; DOI: 10.1038/s41467-024-46370-0 Citation Format: Matteo Bocci, Justin V Joseph, Ulla K Hansen, Marcos Iglesias, Ayako W Pedersen. A TGF-β-directed peptide vaccine induces T cell activation and drives antitumor activity by modulating the architecture of the tumor microenvironment [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B117.