CSF1R inhibition delays cervical and mammary tumor growth in murine models by attenuating the turnover of tumor-associated macrophages and enhancing infiltration by CD8⁺T cells

Abstract

Increased numbers of tumor-infiltrating macrophages correlate with poor disease outcome in patients affected by several types of cancer, including breast and prostate carcinomas. The colony stimulating factor 1 receptor (CSF1R) signaling pathway drives the recruitment of tumor-associated macrophages (TAMs) to the neoplastic microenvironment and promotes the differentiation of TAMs toward a pro-tumorigenic phenotype. Twelve clinical trials are currently evaluating agents that target the CSF1/CSF1R signaling pathway as a treatment against multiple malignancies, including breast carcinoma, leukemia, and glioblastoma. The blockade of CSF1R signaling has been shown to greatly decrease the number of macrophages in a tissue-specific manner. However, additional mechanistic insights are needed in order to understand how macrophages are depleted and the global effects of CSF1R inhibition on other tumor-infiltrating immune cells. Using BLZ945, a highly selective small molecule inhibitor of CSF1R, we show that CSF1R inhibition attenuates the turnover rate of TAMs while increasing the number of CD8+ T cells that infiltrate cervical and breast carcinomas. Specifically, we find that BLZ945 decreased the growth of malignant cells in the mouse mammary tumor virus-driven polyomavirus middle T antigen (MMTV-PyMT) model of mammary carcinogenesis. Furthermore, we show that BLZ945 prevents tumor progression in the keratin 14-expressing human papillomavirus type 16 (K14-HPV-16) transgenic model of cervical carcinogenesis. Our results demonstrate that TAMs undergo a constant turnover in a CSF1R-dependent manner, and suggest that continuous inhibition of the CSF1R pathway may be essential to maintain efficacious macrophage depletion as an anticancer therapy.

Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils

“…In addition, other myeloid populations, such as CSF-1-dependent tumor-associated macrophages (38,39), can impair Tcell function and contribute to immune suppression. In an eloquent study by Elpek et al (40), two different types of tumors with distinct myeloid cell compositions were implanted into the same mouse, and yet the immune compositions were unaffected by the presence of the other tumor type.…”

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.…”

Targeting Suppressive Myeloid Cells Potentiates Checkpoint Inhibitors to Control Spontaneous Neuroblastoma

“…For in vitroblocking experiments, stock solutions were prepared by dissolving BLZ945 or GW2580 (Selleck Chemicals) in DMSO at 10 mmol/L and 1 mmol/L, respectively. For in vivo treatment, BLZ945 was dissolved in 20% Captisol at 16 mg/mL and delivered by daily oral gavage at the dose of 200 mg/kg, according to a previous study (29).…”

“…In malignant conditions, tumor-derived M-CSF is associated with poor survival in various human cancers (26). Thus, targeting strategies against its receptor (CSF-1R) have been extensively explored (27)(28)(29). When included in combinational approaches, blockade of CSF-1R signaling exhibits synergistic effects of various anticancer therapies (30)(31)(32)(33)(34).…”