TGF-β2 antisense oligonucleotide enhances T-cell mediated anti-tumor activities by IL-2 via attenuation of fibrotic reaction in a humanized mouse model of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, with high mortality and recurrence rate. In this study, we generated a human immune system mouse model by transplanting human peripheral blood mononuclear cells into NSG-B2m mice followed by xenografting AsPC-1 cells, after which we assessed the role of transforming growth factor-82 (TGF-82) in T-cell-mediated anti-tumor immunity. We observed that inhibiting the TGF-82 production by TGF-82 antisense oligonucleotide (TASO) combined with IL-2 delays pancreatic cancer growth. Co-treatment of TASO and IL-2 had little effect on the SMAD-dependent pathway, but significantly inhibited the Akt phosphorylation and sequentially activated GSK-38. Activation of GSK-38 by TASO subsequently suppressed 8-catenin and a-SMA expression and resulted in attenuated fibrotic reactions, facilitating the infiltration of CD8 + cytotoxic T lymphocytes (CTLs) into the tumor. TGF-82 inhibition suppressed the Foxp3 + regulatory T-cells in peripheral blood and tumors, thereby enhancing the tumoricidal effects of CTLs associated with increased granzyme B and cleaved caspase-3. Moreover, changes in the T-cell composition in peripheral blood and at the tumor site by TASO and IL-2 induced the increase of pro-inflammatory cytokines such as IFN-y and TNF-a and the decrease of anti-inflammatory cytokines such as TGF-8s. These results indicate that the TGF-82 inhibition by TASO combined with IL-2 enhances the T-cell mediated anti-tumor immunity against SMAD4-mutated PDAC by modulating the tumor-associated fibrosis, suggesting that TASO in combination with IL-2 may be a promising immunotherapeutic intervention for PDAC.

Automated summary

In this study, a human immune system mouse model was generated to investigate the role of TGF-β2 in T-cell-mediated anti-tumor immunity against PDAC. Results showed that inhibiting TGF-β2 production delays pancreatic cancer growth and enhances the infiltration of cytotoxic T lymphocytes (CTLs). TGF-β2 inhibition also suppresses regulatory T-cells and induces pro-inflammatory cytokines. This suggests that TASO combined with IL-2 may be a promising immunotherapeutic intervention for PDAC.