Cancer immunotherapy generally offers limited clinical benefit without coordinated strategies to mitigate the immunosuppressive nature of the tumor microenvironment. Critical drivers of immune escape in the tumor microenvironment include tumor-associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC), which not only mediate immune suppression but also promote metastatic dissemination and impart resistance to cytotoxic therapies. Thus, strategies to ablate the effects of these myeloid cell populations may offer great therapeutic potential. In this report, we demonstrate in a mouse model of pancreatic ductal adenocarcinoma (PDAC) that inhibiting signaling by the myeloid growth factor receptor CSF1R can functionally reprogram macrophage responses that enhance antigen presentation and productive anti-tumor T cell responses. Investigations of this response revealed that CSF1R blockade also upregulated T cell checkpoint molecules, including PDL1 and CTLA4, thereby restraining beneficial therapeutic effects. We found that PD1 and CTLA4 antagonists showed limited efficacy as single agents to restrain PDAC growth, but that that combining these agents with CSF1R blockade potently elicited tumor regressions, even in larger established tumors. Taken together, our findings provide a rationale to reprogram immunosuppressive myeloid cell populations in the tumor microenvironment under conditions that can significantly empower the therapeutic effects of checkpoint-based immunotherapeutics.

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Single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME). Critical obstacles to immunotherapy in PDAC tumors include a high number of tumor-associated immunosuppressive cells and a uniquely desmoplastic stroma that acts as a barrier to T-cell infiltration. We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition using the selective FAK inhibitor VS-4718 significantly limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This delay in tumor progression was associated with dramatically reduced tumor fibrosis, and decreased numbers of tumor-infiltrating immunosuppressive cells. We also found that FAK inhibition rendered the previously unresponsive KPC mouse model responsive to T cell immunotherapy and PD-1 antagonists. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME and renders tumors responsive to immunotherapy.

Tumor-infiltrating immune cells can promote chemoresistance and metastatic spread in aggressive tumors. Consequently, the type and quality of immune responses present in the neoplastic stroma are highly predictive of patient outcome in several cancer types. In addition to host immune responses, intrinsic tumor cell activities that mimic stem cell properties have been linked to chemoresistance, metastatic dissemination and the induction of immune suppression. Cancer stem cells are far from a static cell population; rather, their presence appears to be controlled by highly dynamic processes that are dependent on cues from the tumor stroma. However, the impact immune responses have on tumor stem cell differentiation or expansion is not well understood. In this study, we demonstrate that targeting tumor-infiltrating macrophages and inflammatory monocytes by inhibiting either the myeloid cell receptors CSF1R or CCR2 decreases the number of tumor-initiating cells in pancreatic tumors. Targeting CCR2 or CSF1R improves chemotherapeutic efficacy, inhibits metastasis and increases anti-tumor T-cell responses. Tumor-educated macrophages also directly enhanced the tumor-initiating capacity of pancreatic tumor cells by activating the transcription factor STAT3, thereby facilitating macrophage-mediated suppression of CD8+ T lymphocytes. Together, our findings show how targeting tumor-infiltrating macrophages can effectively overcome therapeutic resistance mediated by tumor-initiating cells.

Summary Background Thirty-five percent of pancreatic cancer patients have unresectable locally advanced pancreatic cancer (LAPC) at diagnosis. Several studies have evaluated systemic chemotherapy with FOLFIRINOX for patients with LAPC. We report a patient-level meta-analysis of LAPC patients treated with FOLFIRINOX as first-line treatment. Methods A systematic literature search was performed in Embase, Medline (ovidSP), Web of Science, Scopus, PubMed Publisher, Cochrane, and Google Scholar. Studies evaluating FOLFIRINOX as first-line treatment for LAPC were included. The primary outcome was overall survival (OS) and secondary outcomes included progression free survival (PFS), and grade 3 or 4 adverse events. We collected patient-level data from all studies that reported survival outcomes. The Kaplan-Meier method was used for survival outcomes. Grade 3 or 4 adverse event rates and the percentage of subsequent (chemo)radiation or resection in eligible studies were pooled in a random effects model. Findings Thirteen eligible studies representing 689 patients were included of whom 355 had LAPC. Eleven studies, representing 315 LAPC patients, reported survival outcomes and were eligible for patient-level meta-analysis. The median OS ranged from 10·0 to 32·7 months across studies with a patient-level median OS of 24·2 months [95% CI: 21·6 - 26·8 months]. The median PFS ranged from 3·0 to 20·4 months across studies with a patient-level median PFS of 15·0 months [95% CI: 13·8 – 16·2 months]. In 10 studies representing 490 patients, 296 Grade 3 or 4 adverse events were reported (i.e. 60·4 events per 100 patients). No death was attributed to FOLFIRINOX toxicity. Subsequent treatments included (chemo)radiation (63·5%) and surgical resection (25·9%). Interpretation Patients with LAPC treated with FOLFIRINOX had a median OS of 24·2 months that is far superior to previously reported OS with gemcitabine. Future research should evaluate these promising results in a randomized controlled trial and determine which patients might benefit from (chemo)radiation or a resection after FOLFIRINOX.