Promoting tumor antigen presentation unleashes therapeutic efficacy of Tgfbr2-deficient TCR-engineered T cells in pancreatic ductal adenocarcinoma

Background: Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with limited therapeutic options. Adoptive cell therapy (ACT) using tumor-reactive T cell receptor-engineered T cells (TCR-T) is a promising therapeutic modality for targeting PDA. However, additional strategies are needed to overcome the suppressive tumor microenvironment (TME) that impairs T cell persistence and function. Tumor growth factor-β (TGFβ) is a prominent immunosuppressive component of the TME, but is also believed to be critical for T cell memory. Methods: We develop aggressive immunocompetent orthotopic KrasLSL-G12D/+;Trp53LSL-R172H/+;p48-Cre (KPC) PDA mouse models to identify obstacles to sustained activity of TCR-T cell therapy targeting the native tumor antigen, mesothelin (Msln). During ACT, we track TCR-T cell fate, function, antitumor effects, and interactions with type I dendritic cells using flow cytometry, two-photon microscopy, and live-cell imaging. Based on an abundance of TGFβ and a halt in TCR-T cell differentiation in orthotopic tumors, TCR-T cells with defective Tgfbr2 are tested in a new model, where peptide-major histocompatibility complex-I (pMHC-I) is incrementally augmented on KPC tumor cells. Results: TCR-T cells accumulated in orthotopic PDA but were rendered dysfunctional despite lacking features of exhaustion. KPC tumor cells express minimal constitutive MHC-I, resulting in suboptimal recognition by TCR-T cells. Modestly increasing pMHC-I on KPC tumor cells restored canonical differentiation of TCR-T cells into PD-1+ progenitor exhausted (TPEX) in PDA, but failed to rescue interferon-γ (IFNγ) production. TGFβ was enriched in tumor nests, and deletion of Tgfbr2 in TCR-T cells enhanced dendritic cell interactions, reduced intratumoral TGFβ deposition, restored IFNγ production, and improved therapeutic efficacy without compromising TCR-T cell longevity or tissue residency. Conclusions: Modestly enhancing tumor-intrinsic pMHC-I unleashes therapeutic efficacy and functionality of Tgfbr2-disrupted TCR-T cells in PDA.