Targeting distinct tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor in solid tumors

In recent years, the cellular microenvironment has emerged as a critical component of solid tumors, comprising a myriad of associated stromal cells that potentiate tumor progression. In particular, the focus of cancer biology has surrounded the complex link between tumor vasculature and inflammation. Angiogenesis is a key process by which tumor cells obtain nutrients for growth and, along with lymphangiogenesis, provides a conduit for tumor dissemination. Inflammation also influences various aspects of tumorigenesis, including initiation and progression to metastasis. This study examines the contributions of vasculature and inflammation to tumor progression using both human xenograft and murine tumor models. We found that angiogenic VEGFR-2 and lymphangiogenic VEGFR-3 signaling differentially regulated prostate cancer growth and metastasis. VEGFR-2 blockade suppressed primary tumor growth and systemic metastasis, but not nodal spread. Conversely, VEGFR-3 blockade greatly reduced both nodal and systemic metastasis without impacting primary tumor growth. These studies demonstrate the potential therapeutic efficacy of targeting both vascular axes in prostate cancer. However, inhibiting tumor vasculature as a single agent therapy has shown marginal results in clinical trials. Therefore, research groups have begun evaluating other therapeutic targets, such as inflammation, to combine with conventional therapies. In particular, tumor-infiltrating myeloid cells (TIMs) are implicated in promoting tumor angiogenesis and suppressing anti-tumor immune responses. We therefore used both genetic and pharmacologic methods to modulate TIMs and evaluated their contributions to tumor progression using several murine tumor models. By targeting colony-stimulating factor-1 receptor (CSF1R), we demonstrated that this signaling pathway is critical for the tumor recruitment of distinct TIM subsets. Inhibiting TIM recruitment via CSF1R blockade resulted in reduced tumor angiogenesis associated with reduced expression of pro-angiogenic and immunosuppressive factors. Combining therapeutic inhibition of CSF1R with anti-angiogenic therapy resulted in synergistic tumor growth reduction. CSF1R blockade also potentially altered macrophage polarization by upregulating MHC class II expression in TIMs and by reducing the tumoral expression of several cytokines and chemokines important for tumor progression. Through this work, we believe that we have contributed significantly to the field of cancer biology, and have highlighted a potentially effective therapeutic strategy for the treatment of solid cancers by simultaneously targeting tumor vasculature and inflammation.