TGF-β RECEPTOR INHIBITION INCREASES PD-L1 EXPRESSION IN PANCREATIC CANCER
Marcus A. Alvarez*, Syed M. Hussain, Rita G. Kansal, Leah Hendrick, Paxton Dickson, Jeremiah Deneve, David Shibata, Evan S. Glazer
Surgery, University of Tennessee Health Science Center, Memphis, TN
Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a malignancy where treatment continues to present significant challenges, and it will likely become the second leading cause of cancer-related deaths in the next few years. Transforming growth factor-β (TGF-β) is a critically important and ubiquitous cytokine that has varied effects on numerous downstream effector molecules. Programmed cell death ligand 1 (PD-L1) is a protein expressed on multiple cells including cancer cells and macrophages that lead to tumoral immune suppression. We hypothesized that modulation of the TGF-β receptor may lead to alterations in PD-L1 expression and help explain the immunosuppressive tumor microenvironment seen in PDAC.
Methods: We retrospectively investigated PD-L1 expression in PDAC tumors from patients with long-term (>30 months) and short-term survival (<6 months) after pancreatic resection with curative intent. We studied the effects of chemotherapy treatment (gemcitabine) and TGF-β receptor inhibition (galunisertib) on PD-L1 expression in PDAC cell lines (Capan-1 and Panc-1 cell lines) with Western blot and in mice implanted with syngeneic PDAC tumors (KPC cells implanted into B6 mice) using immunofluorescence (see Figure, panel A). Treatment groups were 5 mice in each group (PBS control, gemcitabine only, galunisertib only, or gemcitabine + galunisertib).
Results: Tumors from short-term surviving PDAC patients had higher PD-L1 expression compared to long-term surviving patients (P=0.006). In PDAC cell lines, we found that gemcitabine and galunisertib both increased PD-L1 expression compared to PBS treated controls. In mice orthotopically implanted with murine PDAC cells (KPC cell line), gemcitabine and galunisertib treatment decreased tumor burden (P=0.018). Galunisertib alone increased tumor PD-L1 expression compared to controls (P<0.0001) while gemcitabine treatment did not increase PD-L1 expression (P=0.5). Combined gemcitabine and galunisertib increased PD-L1 expression in murine PDAC tumors compared to controls and gemcitabine alone (P<0.001, see Figure).
Conclusions: Our results demonstrate in vivo efficacy for PDAC treatment with combined chemotherapy and TGF-β receptor inhibition, but we also demonstrate a potential mechanism for the development of therapeutic resistance via increased PD-L1 expression. Results supporting these findings were also found in patient samples. Further investigations are ongoing to determine the effects of TGF-β receptor inhibition on tumor associated macrophage PD-L1 expression and the effects of combing anti-PD-L1 therapy, TGF-β receptor inhibition, and chemotherapy.
PD-L1 immunofluorescence (A) was higher in galunisertib (Gal) treated KPC cells orthotopically implanted into immunocompetent B6 mice compared to PBS control or gemcitabine (Gem) treated groups (B).
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