Rationale for multi-epitope TGFβ vaccination in pancreatic cancer: evidence from immunologic and clinical correlates

Transforming growth factor beta (TGFβ) plays a crucial role in pancreatic ductal adenocarcinoma (PDAC) progression by promoting immune suppression, fibrosis, and metastasis. Given its central role in shaping the tumor microenvironment, TGFβ has attracted significant clinical interest as a target for immunotherapy. One promising and innovative approach involves TGFβ-based immune-modulatory vaccines (IMVs). In this study, we explored the immunogenic potential of multiple TGFβ-derived epitopes and assessed the clinical relevance of TGFβ-specific T cells in PDAC patients. We identified T cell responses towards multiple epitopes, TGFβ‑15, TGFβ‑33, and TGFβ‑38, in both healthy donors and PDAC patients, with TGFβ‑33 eliciting particularly robust responses in the patient cohort. These primarily CD4⁺ T cells displayed proinflammatory, as well as notable cytotoxic, properties and recognized target cells in a TGFβ-dependent manner. Moreover, we found that higher baseline frequencies of TGFβ‑33-specific T cells correlated with improved clinical outcomes following combined immune checkpoint inhibitor therapy and radiotherapy. Interestingly, patients with baseline responses to multiple TGFβ-derived epitopes had longer overall and progression-free survival compared to those with responses to none or a single epitope. Using a single mRNA construct encoding multiple TGFβ epitopes, we demonstrated effective activation of T cells specific for distinct TGFβ epitopes. These findings support the potential of a multi-epitope TGFβ-derived immune-modulatory vaccine to enhance anti-tumor immunity, representing a promising strategy to improve therapeutic responses in PDAC.