Abstract 2257: A TGFβ-directed immune-modulatory vaccine induces T cell activation and drives antitumor activity by modulating the tumor microenvironment

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, myeloid cells, and blood vessels) exploit this pathway to support disease progression during tumor evolution. Nonetheless, global inhibition strategies targeting TGFβ pathway in clinical studies thus far fell short of the anticipated success. These clinical observations suggest that TGFβ 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 TGFβ-expressing cells are targeted via a peptide vaccine directed against TGFβ-specific T cell epitopes. This is based on earlier studies reporting the existence of intrinsic T cell immunity against TGFβ in human1,2, thus supporting the rationale for targeting these T cells through a vaccine encoding TGFβ epitopes. To test this approach, we employed a range of murine platforms including the syngeneic Pan02 model of pancreatic adenocarcinoma (PDAC), and a CRISPR/Cas9-driven model of prostate cancer3. Collectively, treatment with the TGFβ vaccine significantly reduced the total tumor burden, without affecting the body weight and overall welfare of the animals. Ex vivo T-cell responses evaluated through interferon (IFN)-γ ELISpot 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, to clarify the mechanism of action, we are implementing the 4T1 model of mammary carcinogenesis to model metastatic disease and exploring spatial relationships to identify which cell types and tissue architectures are pivotal for meaningful responses.In conclusion, our data indicate the efficacy of TGFβ peptide vaccine in eliciting an immune response and tumor growth inhibition in mouse models of cancer. These observations warrant further preclinical investigation to better understand the efficacy and the safety profile of this novel TGFβ-targeting strategy. References: 1. Holmström et al., 2021; DOI: 10.1038/s41423-020-00593-5 2. Mortensen et al., 2021; DOI: 10.1038/s41423-021-00770-0 3. Cai et al., 2024; DOI: 10.1038/s41467-024-46370-0 Citation Format: Justin Vareecal Joseph, Matteo Bocci, Ulla Kring Hansen, Marcos Iglesias, Ayako Wakatsuki Pedersen. A TGFβ-directed immune-modulatory vaccine induces T cell activation and drives antitumor activity by modulating the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2257.