Abstract IA20: Harnessing the immune reaction associated with pancreas carcinoma for therapy

Abstract

Abstract Macrophages are a prominent feature of many solid malignancies. However, their presence within tumors most often portends a poor prognosis due to their ability to promote tumor growth, invasion and metastasis. In pancreatic ductal adenocarcinoma (PDAC), macrophages are observed at disease conception and are present throughout all stages of tumor development including metastasis. Strategies to target macrophages in cancer have focused on approaches to 1) deplete macrophages or their precursors, 2) block myeloid cell recruitment to tumor tissues, and 3) inhibit tumor-promoting functions directed by macrophages. However, macrophage biology is largely dependent on cues received from the surrounding microenvironment such that macrophages can be polarized with either tumor promoting or tumor suppressing properties. In this regard, we have previously demonstrated that macrophages can be redirected in vivo with anti-tumor properties leading to depletion of tumor-associated fibrosis and major tumor regressions in both mice and humans. Macrophages responding to systemic activation of the CD40 pathway using an agonist CD40 monoclonal antibody were required for tumor regressions observed in a spontaneous model of murine PDAC. However, not all murine PDAC lesions responded to CD40 therapy. Similarly, treatment response heterogeneity detected on 18FDG-PET/CT was observed in patients with newly diagnosed chemotherapy-naive PDAC who were treated with a fully human CD40 agonist. These findings demonstrate that macrophages associated with PDAC can be harnessed for therapy but also emphasize the importance of tumor intrinsic properties in regulating the efficacy of macrophage immunotherapy in PDAC. Current studies will be presented that investigate 1) the mechanism of action by which macrophages facilitate stromal depletion and 2) potential mechanisms of resistance to macrophage immunotherapy in PDAC. Citation Format: Gregory L. Beatty. Harnessing the immune reaction associated with pancreas carcinoma for therapy. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr IA20.