Background and Major Goals:

The prognosis for pancreatic cancer 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 tumors. Our own work has shown that inhibiting CSF1R can vastly improve responses to chemotherapy and decrease metastatic spread in mammary 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 pancreatic cancer.

Progress Year 1:

Using pre-clinical models of PDAC, we have demonstrate that inhibition of colony stimulating factor 1 receptor (CSF1R) signaling functionally reprograms macrophage responses to enhance antigen presentation, thereby stimulating anti-tumor T cell responses. However, this immune reprograming also leads to the up-regulation of T cell checkpoint molecules, including Programed Cell Dealth Ligand 1 (PDL1) and Cytotoxic T-Lymphocyte Antigen 4 (CTLA4), which significantly limits the potential of the CSF1R blockade to induce anti-tumor responses and restrain PDAC tumor progression. While both PD1 and CTLA4 antagonists show limited efficacy as single agents to restrain PDAC growth in a mouse model, the combination of these agents with CSF1R blockade achieves disease regression even in well-established tumors. These data suggest that reprograming myeloid responses through CSF1R blockade can improve the efficacy of checkpoint-based immunotherapeutics in pancreatic cancer.

Goals for Year 2:

The major goal for year 2 is to understand the molecular mechanism by which CSF1R blockade improved responses to checkpoint based immunotherapy. Our belief is that by understanding how this new therapeutic combination works we can identify the patient populations most likely to benefit from this approach and/or alternative approaches that limit potential toxicities of these immunotherapies in patients.