Role of TGF-beta in pancreatic ductal adenocarcinoma progression and PD-L1 expression

Purpose The transforming growth factor-beta (TGF-beta) pathway plays a paradoxical, context-dependent role in pancreatic ductal adenocarcinoma (PDAC): a tumor-suppressive role in non-metastatic PDAC and a tumor-promotive role in metastatic PDAC. We hypothesize that non-SMAD-TGF-beta signaling induces PDAC progression. Methods We investigated the expression of non-SMAD-TGF-beta signaling proteins (pMAPK14, PD-L1, pAkt and c-Myc) in patient-derived tissues, cell lines and an immunocompetent mouse model. Experimental models were complemented by comparing the signaling proteins in PDAC specimens from patients with various survival intervals. We manipulated models with TGF-beta, gemcitabine (DNA synthesis inhibitor), galunisertib (TGF-beta receptor inhibitor) and MK-2206 (Akt inhibitor) to investigate their effects on NF-kappa B, beta-catenin, c-Myc and PD-L1 expression. PD-L1 expression was also investigated in cancer cells and tumor associated macrophages (TAMs) in a mouse model. Results We found that tumors from patients with aggressive PDAC had higher levels of the non-SMAD-TGF-beta signaling proteins pMAPK14, PD-L1, pAkt and c-Myc. In PDAC cells with high baseline beta-catenin expression, TGF-beta increased beta-catenin expression while gemcitabine increased PD-L1 expression. Gemcitabine plus galunisertib decreased c-Myc and NF-kappa B expression, but induced PD-L1 expression in some cancer models. In mice, gemcitabine plus galunisertib treatment decreased metastases (p = 0.018), whereas galunisertib increased PD-L1 expression (p < 0.0001). In the mice, liver metastases contained more TAMs compared to the primary pancreatic tumors (p = 0.001), and TGF-beta increased TAM PD-L1 expression (p < 0.05). Conclusions In PDAC, the non-SMAD-TGF-beta signaling pathway leads to more aggressive phenotypes, TAM-induced immunosuppression and PD-L1 expression. The divergent effects of TGF-beta ligand versus receptor inhibition in tumor cells versus TAMs may explain the TGF-beta paradox. Further evaluation of each mechanism is expected to lead to the development of targeted therapies.