Targeting Tumor-Infiltrating Macrophages Decreases Tumor-Initiating Cells, Relieves Immunosuppression, and Improves Chemotherapeutic Responses

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. 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.

Timing of CSF-1/CSF-1R signaling blockade is critical to improving responses to CTLA-4 based immunotherapy

“…16,18,22,23,25,[33][34][35][36] Early studies demonstrated a critical role of CSF-1R on tumor-associated macrophage (TAM) infiltration of spontaneous murine breast tumors and human breast cancer xenografts. These studies showed reduced angiogenesis and delayed tumor progression to metastasis upon depletion or inhibition of CSF-1R-expressing TAMs.…”

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

“…Similarly, when paclitaxel is used with an inhibitor blocking TAM-derived cathepsins, the total lung metastatic burden of MMTV-PyMT mice is lowered [24]. In orthotopic pancreatic tumor transplants, blockade of TAMs and monocytes via CSF1R or CCR2 inhibitors synergizes with gemcitabine and paclitaxel to slow cancer growth and to reduce peritoneal metastasis [29]. Like TAMs in MMTV-PyMT mammary tumors [22], TAMs from these pancreatic tumor transplants suppress CD8 + T cell activation to foster chemoresistance [29].…”

“…In orthotopic pancreatic tumor transplants, blockade of TAMs and monocytes via CSF1R or CCR2 inhibitors synergizes with gemcitabine and paclitaxel to slow cancer growth and to reduce peritoneal metastasis [29]. Like TAMs in MMTV-PyMT mammary tumors [22], TAMs from these pancreatic tumor transplants suppress CD8 + T cell activation to foster chemoresistance [29]. Studies in xenograft tumor models using human breast cancer cell lines have also shown that CSF1 neutralization together with a triple chemotherapy modality (cyclophosphamide, methotrexate, and 5-FU) reverses chemoresistance [30].…”

“…The studies above combining chemotherapy with TAM blockade show only a transient effect on tumor growth; these tumors do not regress and they eventually grow out [22,23,29,30]. The inherent flexibility and redundancy of the immune system lends itself to potential deleterious feedback mechanisms in which the functions of a depleted population are reinstated by another population.…”

“…Neutralization of Angiopoietin 2 (ANGPT2) also reduces metastasis in breast cancer models by preventing TAM association with endothelial cells and angiogenesis [140] as well as CCL2-dependent recruitment of monocytes to metastatic lesions in lung [144,145]. TAMs resident in pancreatic tumors suppress CD8 + T cell functions, and targeting TAMs via anti-CSF1R together with gemcitabine decreases liver metastasis through reactivation of CD8 + T cells [29]. Experiments carried out in melanoma metastasis models have shown that the BRAF inhibitor, PLX4720, and the cKIT inhibitor, imatinib, are effective against lung metastases via an NK cell-dependent mechanism [123,128].…”