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

ABSTRACT

PURPOSE: The transforming growth factor-beta (TGF-ß) 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-ß signaling induces PDAC progression. METHODS: We investigated the expression of non-SMAD-TGF-ß 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-ß, gemcitabine (DNA synthesis inhibitor), galunisertib (TGF-ß receptor inhibitor) and MK-2206 (Akt inhibitor) to investigate their effects on NF-κB, ß-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-ß signaling proteins pMAPK14, PD-L1, pAkt and c-Myc. In PDAC cells with high baseline ß-catenin expression, TGF-ß increased ß-catenin expression while gemcitabine increased PD-L1 expression. Gemcitabine plus galunisertib decreased c-Myc and NF-κB 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-ß increased TAM PD-L1 expression (p < 0.05). CONCLUSIONS: In PDAC, the non-SMAD-TGF-ß signaling pathway leads to more aggressive phenotypes, TAM-induced immunosuppression and PD-L1 expression. The divergent effects of TGF-ß ligand versus receptor inhibition in tumor cells versus TAMs may explain the TGF-ß paradox. Further evaluation of each mechanism is expected to lead to the development of targeted therapies.