Abstract IA21: Myeloid cells are required for PD-1/PD-L1 checkpoint activation and the establishment of an immune-suppressive environment in pancreatic cancer

Autor: Kristen B. Long, Ashley Velez-Delgado, Gregory L. Beatty, Kevin Flannagan, Marina Pasca di Magliano, Flor M. Mendez, Esha Mathew, Andrew D. Rhim, Yaqing Zhang, Dongjun Li, Diane M. Simeone
Rok vydání: 2016
Předmět:
Zdroj: Cancer Research. 76:IA21-IA21
ISSN: 1538-7445
0008-5472
DOI: 10.1158/1538-7445.panca16-ia21
Popis: Pancreatic cancer is characterized by the accumulation of a fibro-inflammatory stroma. Accumulation of the stroma is already evident surrounding Pancreatic Intraepithelial Neoplasias (PanINs), common precursor lesions to pancreatic cancer (Hezel et al., 2006). The stroma is abundantly infiltrated by immune cells, and myeloid cells are a predominant population (Clark et al., 2007). Different myeloid subsets have been correlated with tumor promotion and unmasking of anti-tumor immunity (Liou et al., 2015; Long et al., 2016; Mitchem et al., 2013; Stromnes et al., 2014). Both PanINs and pancreatic cancer and commonly associated with oncogenic mutations in the Kras gene (Biankin et al., 2012; Jones et al., 2010; Kanda et al., 2012). Expression of oncogenic Kras in the pancreas of genetically engineered mice recapitulates the PanIN to pancreatic cancer progression, including the accumulation of fibrotic stroma (Hingorani et al., 2003). We have described a mouse model that allows inducible and reversible expression of oncogenic Kras in the pancreas, the iKras* mouse. Inactivation of oncogenic Kras during the PanIN stage or in cancer leads to regression of the epithelial lesions as well as to remodeling of the stroma, indicating that the accumulation of the stroma is regulated by signals derived from oncogenic Kras-expressing epithelial cells (Collins et al., 2012a). In the current study, we have investigated the interaction between epithelial cells and myeloid cells that infiltrate the pancreas. For this purpose, we have used a combination of genetically engineered mice (iKras*p53* mice (Collins et al., 2012b)) and transplantation approaches into CD11b-DTR mice (Duffield et al., 2005), that allow depletion of myeloid cells upon administration of Diphtheria Toxin. Our results show that the infiltration and polarization of macrophages in the pancreas depends on signals derived from oncogenic Kras-expressing epithelial cells, either directly or through activation of a pro-inflammatory subset of stromal fibroblasts. Conversely, myeloid cells infiltration is required for the progression of PanINs and pancreatic cancer. Depletion of myeloid cells prevented KrasG12D driven pancreatic cancer initiation. In pre-established tumors, myeloid cell depletion resulted in arrest of growth or tumor regression. We observed that tumor progression was dependent on myeloid cell-mediated blockade of CD8+ T cell anti-tumor activity. Furthermore, myeloid cells regulate the expression of the Programmed death-ligand 1 (PD-L1) in tumor cells in an EGFR/MAPK dependent manner. Our results show that myeloid cells regulate a complex network of signals that ensure immune suppression within the pancreatic cancer microenvironment. 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IFNgamma and CCL2 Cooperate to Redirect Tumor-Infiltrating Monocytes to Degrade Fibrosis and Enhance Chemotherapy Efficacy in Pancreatic Carcinoma. Cancer Discov. Mitchem, J. B., Brennan, D. J., Knolhoff, B. L., Belt, B. A., Zhu, Y., Sanford, D. E., Belaygorod, L., Carpenter, D., Collins, L., Piwnica-Worms, D., et al. (2013). Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res 73, 1128-1141. Stromnes, I. M., Brockenbrough, J. S., Izeradjene, K., Carlson, M. A., Cuevas, C., Simmons, R. M., Greenberg, P. D., and Hingorani, S. R. (2014). Targeted depletion of an MDSC subset unmasks pancreatic ductal adenocarcinoma to adaptive immunity. Gut. Citation Format: Yaqing Zhang, Esha Mathew, Ashley Velez-Delgado, Kristen B. Long, Dongjun Li, Flor M. Mendez, Kevin Flannagan, Andrew D. Rhim, Diane M. Simeone, Gregory L. Beatty, Marina Pasca di Magliano.{Authors}. Myeloid cells are required for PD-1/PD-L1 checkpoint activation and the establishment of an immune-suppressive environment in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr IA21.
Databáze: OpenAIRE
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