Date Published: February 6, 2019
Publisher: Public Library of Science
Author(s): Andrew J. Gunderson, Tomoko Yamazaki, Kayla McCarty, Michaela Phillips, Alejandro Alice, Shelly Bambina, Lauren Zebertavage, David Friedman, Benjamin Cottam, Pippa Newell, Michael J. Gough, Marka R. Crittenden, Pieter Van der Veken, Kristina H. Young, Murray Korc.
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a fibrotic stroma with a poor lymphocyte infiltrate, in part driven by cancer-associated fibroblasts (CAFs). CAFs, which express fibroblast activation protein (FAP), contribute to immune escape via exclusion of anti-tumor CD8+ T cells from cancer cells, upregulation of immune checkpoint ligand expression, immunosuppressive cytokine production, and polarization of tumor infiltrating inflammatory cells. FAP is a post-proline peptidase selectively expressed during tissue remodeling and repair, such as with wound healing, and in the tumor microenvironment by cancer-associated fibroblasts. We targeted FAP function using a novel small molecule inhibitor, UAMC-1110, and mice with germline knockout of FAP and concomitant knock-in of E. coli beta-galactosidase. We depleted CAFs by adoptive transfer of anti-βgal T cells into the FAP knockout animals. Established syngeneic pancreatic tumors in immune competent mice were targeted with these 3 strategies, followed by focal radiotherapy to the tumor. FAP loss was associated with improved antigen-specific tumor T cell infiltrate and enhanced collagen deposition. However, FAP targeting alone or with tumor-directed radiation did not improve survival even when combined with anti-PD1 therapy. Targeting of CAFs alone or in combination with radiation did not improve survival. We conclude that targeting FAP and CAFs in combination with radiation is capable of enhancing anti-tumor T cell infiltrate and function, but does not result in sufficient tumor clearance to extend survival.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis characterized by a fibrotic stroma and poor immune infiltrate. PDAC is relatively radioresistant with poor drug penetrance and elevated levels of hypoxia limiting the efficacy of chemoradiotherapy. Radiation therapy is a targeted cytotoxic modality; however, its efficacy can be limited in part by contributions from the tumor stroma. An additional benefit of radiation is its ability to expose tumor antigen and create a focal inflammatory response[2–4]. The efficacy of high-dose radiation is in part dependent on CD8+ T cells[1,5,6]. Therefore, radioresistance can be driven by components in the tumor stroma resulting in neovascularization creating hypoxic regions and alterations in the immune environment impairing CD8+ T cell infiltration and function.
Hallmarks of immune suppression in PDAC include suppressive immune infiltrate, scant cytotoxic T cell infiltrate, and a dense desmoplastic stroma. The inhibitory immune cells include M2 macrophages, MDSCs, and certain B cell populations which contribute immunosuppressive cytokines limiting the efficacy of antitumor immune responses by the few infiltrating CD8+ T cells. The desmoplastic stroma promotes angiogenesis, distorts normal architecture into a dense fibrotic matrix limiting immune infiltrate and leading to pro-tumor polarization of immune cells, as well as tumor cell invasion (reviewed in). Key contributors to the deposition and development of the desmoplastic stroma are pancreatic stellate cells, or CAFs, and B cells.