Abstract B83: Targeting tumor-infiltrating macrophages decreases pancreatic tumor-initiating cells and improves chemotherapeutic responses by relieving immune suppression.

Abstract

Abstract 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. Far from being a static cell population, the presence of cancer stem cells appears to be controlled by highly dynamic processes that are dependent on cues from the tumor stroma. However, the impact that immune responses have on the differentiation or expansion of tumor stem cells is not well understood. In this study, we demonstrate that targeting tumor-infiltrating macrophages and inflammatory monocytes by either inhibition of colony stimulating factor-1 receptor (CSF1R) or chemokine (C-C motif) receptor 2 (CCR2) decreases the number of tumor-initiating cells in pancreatic tumors. Targeting CCR2 or CSF1R improves chemotherapeutic efficacy, inhibits metastasis, and increases antitumor T-cell responses. We also found that tumor-educated macrophages could directly enhance the tumor-initiating capacity of pancreatic tumor cells through the activation of signal transducer and activator of transcription 3 (STAT3). In turn, these STAT3-activated tumor-initiating cells facilitate macrophage-mediated suppression of CD8+ T lymphocytes. These data suggest that targeting tumor-infiltrating macrophages is an effective strategy for overcoming therapeutic resistance due to the presence of tumor-initiating cells. Citation Format: Jonathan B. Mitchem, Donal J. Brennan, Dominic E. Sanford, Brett L. Knolhoff, Yu Zhu, Belt Brian, Andrea Wang-Gillam, Peter Goedegebuure, David C. Linehan, David G. DeNardo. Targeting tumor-infiltrating macrophages decreases pancreatic tumor-initiating cells and improves chemotherapeutic responses by relieving immune suppression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B83.