Abstract LB-205: Myeloid cells are required to establish an immune-suppressive regulatory network in pancreatic cancer by activating the PD-1/PD-L1 checkpoint

Abstract

Abstract Background: Pancreatic cancer is characterized by the accumulation of a fibro-inflammatory stroma. Myeloid cells are a predominant population within the stroma. Different myeloid cell subsets have been correlated with tumor promotion and unmasking of anti-tumor immunity. Objective: The goal of this study was to determine the effect of myeloid cell depletion on the onset and progression of pancreatic cancer, and to understand the relationship between myeloid cells and T cell infiltration and activity within the pancreatic cancer microenvironment. Methods: Primary mouse pancreatic cancer cells were transplanted in CD11b-DTR mice. CD11b+ cells (most myeloid cell populations) were depleted by Diphtheria Toxin treatment; either at the time of tumor implantation or after tumors had formed. Results Depletion of myeloid cells delayed tumor initiation. In pre-established tumors, myeloid cell depletion resulted in arrest of growth or tumor regression. We observed that tumor regression was dependent myeloid cell-mediated blockade of CD8+ T cell anti-tumor activity. We investigated the mechanism of this inhibition. We found that myeloid cells regulate expression of the immune checkpoint ligand Programmed death-ligand 1 (PD-L1) in the tumor cells in an EGFR/MAPK dependent manner. Conclusions: Our results show that myeloid cells regulate a complex network of signals that ensure immune suppression within the pancreatic cancer microenvironment. Moreover, we show that depletion of the myeloid cell population is sufficient to restore anti-tumor immunity mediated by CD8+ T cells, a finding with implications for the design of immune therapies for pancreatic cancer. Citation Format: YAQING ZHANG, ESHA MATHEW, FLOR MENDEZ, KEVIN FLANNAGAN, DIANE SIMEONE, MARINA PASCA DI MAGLIANO. Myeloid cells are required to establish an immune-suppressive regulatory network in pancreatic cancer by activating the PD-1/PD-L1 checkpoint. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-205. doi:10.1158/1538-7445.AM2015-LB-205