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 of these metastatic tumors 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 and increasing the presence of cancer stem cells. 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 colony-stimulating factor 1 receptor (CSF1R). Previous studies have shown that genetic loss of colony stimulating factor-1, a critical cytokine for the recruitment, survival, and activation of macrophages, can decease the progression of mammary and neuroendocrine pancreatic tumors. Our own work has shown that inhibiting CSF1R can vastly improve responses to chemotherapy and decrease metastatic spread in pancreatic tumor models. We have now extended these observations and demonstrated that CSF1R inhibition 1) rapidly reprograms tumor-infiltrating macrophage responses, 2) decreases the frequency of tumor initiating cells, and 3) leads to recovery of anti-tumor cytotoxic responses by neutrophils and T lymphocytes. In so doing, CSF1R inhibition reprograms the tumor microenvironment to increase responses to chemotherapy and decrease metastatic spread. Thus, our hypothesis is that blockade of CSF1R signaling reprograms the tumor microenvironment to improve responses to chemo- and immunotherapy. The long-term goals of the proposed studies are to initiate new clinical trials testing this approach in metastatic PC. However, in order to inform these trials and test our overall hypothesis the following specific aims are critical.
Aim 1 : Determine the mechanisms by which macrophages regulate metastatic relapse.
Aim 2 : Determine the functional role of CSF1R blockade in granulocyte reprogramming.
Aim 3 : Determine the optimum therapeutic regimen for targeting CSF1R to improve immunotherapy.
These Aims form the basis of our proposed studies, which will use a combination of clinically translatable agents and genetic mouse models to: 1) fundamentally understand the biological underpinnings by which myeloid cells regulate chemotherapeutic response. And 2) to identify and validate targets to exploit these biological processes for therapeutic benefit. Thus, this application will develop targeted inhibition of CSF1R as a novel immunotherapeutic agent to improve outcomes for pancreatic cancer patients.

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 colony-stimulating factor 1 receptor (CSF1R) signaling as a significant regulator of immune-mediated chemoprotection and in order to develop this approach for clinical application, these studies will test the ability of CSF1R-inhibition to improve responses to chemo- and immunotherapy in metastatic pancreatic cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA177670-01A1
Application #
8694239
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Muszynski, Karen
Project Start
2014-04-01
Project End
2019-02-28
Budget Start
2014-04-01
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$316,178
Indirect Cost
$108,678
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130