The prognosis for pancreatic cancer (PC) patients is dismal, with a 5-year survival rate of less than 6%. This is in part due to the propensity of PC to metastasize prior to disease detection and the resistance to cytotoxic therapies. A significant portion of therapeutic resistance in pancreatic cancers comes from the support of a unique tumor microenvironment. This tumor microenvironment includes significant numbers of infiltrating myeloid cells including tumor-associated macrophages, which exacerbate responses to therapy by inducing immunosuppression. Thus, where clinically feasible reprogramming the immune microenvironment would improve responses to cytotoxic therapy even in resistant tumors. One unique approach to this problem is to target the C-C chemokine receptor type 2 (CCR2). Signaling through C-C chemokine receptor type 2 (CCR2) is critical to the mobilization of IM and their recruitment to inflamed tissue. Our preliminary and published findings clearly show that blockade of IM mobilization using a novel CCR2 inhibitor, PF-04136309 slows tumor progression and prevents metastasis in mouse models of PC. Thus, selective targeting of inflammatory monocytes holds significant promise for the treatment of PC. Based on this exciting and provocative preliminary data, we have initiated a Phase Ib clinical trial targeting th CCR2 signaling pathway in patients with locally-advanced pancreas cancer. While targeting CCR2 holds strong clinical potential for bolstering cytotoxic therapy it may be even more promising in combination with immunotherapy. Strikingly, our studies have found that CCR2 blockade overcomes immune suppression to re-initiates anti- tumor responses by CD8+ CTLs. However, CCR2 inhibition also leads to up-regulation T cell checkpoint pathways such as Programmed Cell Death 1 (PD1) ligands and Cytotoxic T-Lymphocyte Antigen 4 (CTLA4). These data suggest that the combination of CCR2 inhibition and anti-CTLA4 and/or PD1 based immunotherapy would be highly effective at generating the type of durable anti-tumor immune responses necessary to impact patient survival. Thus, building on our published work, new preliminary data, and samples from our existing clinical trial this grant will focus on understanding and exploiting the mechanisms by which CCR2 blockade reprograms the pancreatic tumor microenvironment to bolster anti-tumor immunity. Our overall hypothesis is that blockade of CCR2 signaling reprograms the tumor microenvironment to improve responses to immunotherapy. To test this, we will: 1) Determine the optimum therapeutic regimen for targeting CCR2 to improve immunotherapy. 2) Determine the effect of CCR2 blockade on T lymphocyte responses in human pancreatic cancer Summary: The proposed research will assess the efficacy of targeting CCR2 to improve immunotherapy, thus allowing this strategy to be integrated into future clinical trials. At the same time our studies will improve our understanding of the mechanism(s) by which CCR2 blockade improves CTL responses in humans and mice.

Public Health Relevance

The response of pancreatic cancer patients to current cytotoxic therapies is dismal;this is in part due the support of a unique immune microenvironment which blocks effective therapy. Therefore, the reprogramming immune responses to facilitate anti-tumor immunity would be effective at extending survival in pancreatic cancer patients. We have identified C-C chemokine receptor type 2 (CCR2) signaling as a significant regulator of myeloid mediated immunosuppression and in order to develop this approach for clinical application, these studies will test the ability of CCR2-inhibition to improv responses to immunotherapy in pancreatic cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Timmer, William C
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
Zip Code
Zhang, Daoxiang; Li, Lin; Jiang, Hongmei et al. (2017) Constitutive IRAK4 Activation Underlies Poor Prognosis and Chemoresistance in Pancreatic Ductal Adenocarcinoma. Clin Cancer Res 23:1748-1759
Su, Xinming; Esser, Alison K; Amend, Sarah R et al. (2016) Antagonizing Integrin ?3 Increases Immunosuppression in Cancer. Cancer Res 76:3484-95
D'Amico, Lucia; Mahajan, Sahil; Capietto, Aude-Hélène et al. (2016) Dickkopf-related protein 1 (Dkk1) regulates the accumulation and function of myeloid derived suppressor cells in cancer. J Exp Med 213:827-40
Jiang, Hong; Hegde, Samarth; Knolhoff, Brett L et al. (2016) Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat Med 22:851-60
Nywening, Timothy M; Wang-Gillam, Andrea; Sanford, Dominic E et al. (2016) Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet Oncol 17:651-62
Demehri, Shadmehr; Cunningham, Trevor J; Manivasagam, Sindhu et al. (2016) Thymic stromal lymphopoietin blocks early stages of breast carcinogenesis. J Clin Invest 126:1458-70
Zhu, Yu; Hawkins, William G; DeNardo, David G (2015) Regramming myeloid responses to improve cancer immunotherapy. Oncoimmunology 4:e974399
Zhong, Hua; Sanchez, Cesar; Spitrzer, Dirk et al. (2015) Correction: Synergistic Effects of Concurrent Blockade of PI3K and MEK Pathways in Pancreatic Cancer Preclinical Models. PLoS One 10:e0127365
Shiao, Stephen L; Ruffell, Brian; DeNardo, David G et al. (2015) TH2-Polarized CD4(+) T Cells and Macrophages Limit Efficacy of Radiotherapy. Cancer Immunol Res 3:518-25
Zhu, Yu; Knolhoff, Brett L; Meyer, Melissa A et al. (2014) CSF1/CSF1R blockade reprograms tumor-infiltrating macrophages and improves response to T-cell checkpoint immunotherapy in pancreatic cancer models. Cancer Res 74:5057-69

Showing the most recent 10 out of 14 publications