Abstract 115: A CD40 agonist potentiates the efficacy and immune-stimulatory capacity of chemotherapy in combination with a focal adhesion kinase inhibitor in a mouse model of pancreatic ductal adenocarcinoma
Authors: Stone Meredith L. , Graham Kathleen , Aldridge Daniel , Jain Kanika , Pan Xiaoqing , Pachter Jonathan , Beatty Gregory 
Published: August 2019

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) has proved to be remarkably resistant to immune based therapies. This resistance may be in part due to the PDAC microenvironment that is characterized by an abundance of myeloid cells, a scarcity of effector T cells and a dense fibrotic stroma. Activation of focal adhesion kinase (FAK) signaling promotes the formation of an immune suppressive microenvironment in PDAC, and FAK inhibition (FAKi) can reduce stromal density and improve the sensitivity of tumors to chemotherapy. Likewise, CD40-dependent innate immune responses can disrupt the stromal matrix that surrounds the tumor and sensitize tumors to the cytotoxic and immune-stimulatory effects of chemotherapy. Here, we hypothesize that FAK signaling may limit the efficacy of CD40 agonists and thus, FAK and CD40 may be non-redundant pathways that can be targeted for improving outcomes to cytotoxic chemotherapy.

METHODS: For our studies, we used polyclonal pancreatic cancer cells derived from the KrasG21D/+; Trp53R172H/+; Pdx-1 Cre (KPC) genetic mouse model of PDAC, which recapitulates many of the features of human disease, including a paucity of T cells and a robust infiltration of myeloid cells. KPC cell lines were subcutaneously implanted into syngeneic C57BL/6 mice. Approximately 2 weeks after tumor implantation, mice were block randomized to receive treatment with a CD40 agonist (FGK45) or PBS administered prior to (5 days prior) or after (2 days post) gemcitabine (gem) chemotherapy with or without FAKi.

RESULTS: We first examined the impact of chemotherapy in combination with FAKi to enhance the immune stimulatory capacity of a CD40 agonist. We found that the triple combination (FAKi+gem→FGK45), in which FGK45 is given after FAKi and gem, significantly reduced tumor growth, increased tumor necrosis, and improved survival compared to FAKi alone or gem→FGK45. In this treatment setting, both gem→FGK45 and the triple combination significantly increased the CD8+/Foxp3+ ratio and the proliferation of CD8+ T cells in tumors. We next examined the capacity of a CD40 agonist to enhance the efficacy of chemotherapy, with or without FAKi. The triple combination (FGK45→FAKi+gem), in which FGK45 is given before FAKi and gem, significantly inhibited tumor growth and improved survival compared to all other groups. In this treatment setting, both FGK45→FAKi+gem and FGK45→gem increased the number and proliferation of CD3+ T cells in tumors. Importantly, the triple combination significantly increased the CD8+/Foxp3+ ratio compared to FGK45→Gem, which may account in part for the improvement in tumor response.

CONCLUSION: FAK and CD40 signaling are non-redundant pathways that can be targeted to reverse immune suppressive features in the tumor microenvironment and improve PDAC sensitivity to chemotherapy.

Citation Format: Meredith L. Stone, Kathleen Graham, Daniel Aldridge, Kanika Jain, Xiaoqing Pan, Jonathan Pachter, Gregory Beatty. A CD40 agonist potentiates the efficacy and immune-stimulatory capacity of chemotherapy in combination with a focal adhesion kinase inhibitor in a mouse model of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 115.