The efficacy of adoptive cell therapy for solid tumours is hampered by the poor accumulation of the transferred T cells in tumour tissue. Here, we show that the forced expression of the C-X-C chemokine receptor type 6 (CXCR6, whose ligand is highly expressed by human and murine pancreatic cancer cells and by tumour-infiltrating immune cells) in antigen-specific T cells enhanced the recognition and lysis of pancreatic cancer cells and the efficacy of adoptive cell therapy for pancreatic cancer. In mice with subcutaneous pancreatic tumours treated with T cells with either a transgenic T-cell receptor or a murine chimeric antigen receptor targeting the tumour-associated antigen epithelial cell-adhesion molecule, and in mice with orthotopic pancreatic tumours or patient-derived xenografts treated with T cells expressing a chimeric antigen receptor targeting mesothelin, the T cells exhibited enhanced intratumoral accumulation, exerted sustained antitumoral activity and prolonged animal survival only when co-expressing CXCR6. Arming tumour-specific T cells with tumour-specific chemokine receptors may represent a promising strategy for the realization of adoptive cell therapy for solid tumours.

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Background T cell receptor fusion constructs (TRuC) consist of an antibody-based single chain variable fragment (scFv) fused to a T cell receptor chain (TCR) and allow recognition of cancer cells in an HLA-independent manner. Unlike chimeric antigen receptors (CAR), TRuC are integrated into the TCR complex resulting in a functional chimera with novel specificity, whilst retaining TCR signaling. To further enhance anti-tumor function, we expressed a PD-1-CD28 fusion receptor in TRuC T cells aiming to prevent tumor-induced immune suppression and T cell anergy. Methods The activation level of engineered T cells was investigated in co-culture experiments with tumor cells followed by quantification of released cytokines using ELISA. To study T cell-mediated tumor cell lysis in vitro, impedance-based real-time tumor cell killing and LDH release was measured. Finally, two xenograft mouse cancer models were employed to explore the therapeutic potential of engineered T cells. Results In co-culture assays, co-expression of PD-1-CD28 enhanced cytokine production of TRuC T cells. This effect was dependent on PD-L1 to PD-1-CD28 interactions, as blockade of PD-L1 amplified IFN-γ production in unmodified TRuC T cells to a greater level compared to TRuC-PD-1-CD28 T cells. In vivo, PD-1-CD28 co-expression supported the anti-tumor efficacy of TRuC T cells in two xenograft mouse cancer models. Conclusion Together, these results demonstrate the therapeutic potential of PD-1-CD28 co-expression in TRuC T cells to prevent PD-L1-induced T cell hypofunction.