Colony stimulating factor 1 receptor blockade improves the efficacy of chemotherapy against human neuroblastoma in the absence of T lymphocytes. Issue 6 (7th May 2018) - Webb, Matthew W.
Abstract : Tumor‐associated macrophages can promote growth of cancers. In neuroblastoma, tumor‐associated macrophages have greater frequency in metastatic versus loco‐regional tumors, and higher expression of genes associated with macrophages helps to predict poor prognosis in the 60% of high‐risk patients who have MYCN ‐non‐amplified disease. The contribution of cytotoxic T‐lymphocytes to anti‐neuroblastoma immune responses may be limited by low MHC class I expression and low exonic mutation frequency. Therefore, we modelled human neuroblastoma in T‐cell deficient mice to examine whether depletion of monocytes/macrophages from the neuroblastoma microenvironment by blockade of CSF‐1R can improve the response to chemotherapy. In vitro, CSF‐1 was released by neuroblastoma cells, and topotecan increased this release. In vivo, neuroblastomas formed by subcutaneous co‐injection of human neuroblastoma cells and human monocytes into immunodeficient NOD/SCID mice had fewer human CD14 + and CD163 + cells and mouse F4/80 + cells after CSF‐1R blockade. In subcutaneous or intra‐renal models in immunodeficient NSG or NOD/SCID mice, CSF‐1R blockade alone did not affect tumor growth or mouse survival. However, when combined with cyclophosphamide plus topotecan, the CSF‐1R inhibitor BLZ945, either without or with anti‐human and anti‐mouse CSF‐1 mAbs, inhibited neuroblastoma growth and synergistically improved mouse survival. These findings indicate that depletion of tumor‐associated macrophages from neuroblastomas can be associated with increased chemotherapeutic efficacy without requiring a contribution from T‐lymphocytes, suggesting the possibility that combination of CSF‐1R blockade with chemotherapy might be effective in patients who have limited anti‐tumor T‐cell responses. Abstract : What's new? Monocytes and macrophages rely on colony stimulating factor‐1 (CSF‐1) and its receptor, CSF‐1R, for recruitment and survival in the tumor microenvironment. Moreover, CSF‐1 expression is associated with poor prognosis in certain cancer types. This work shows that after treatment with the chemotherapeutic agent topotecan, neuroblastoma cells increase CSF‐1 release. In immunodeficient mice with neuroblastomas induced by co‐injection of human neuroblastoma cells and human monocytes, BLZ945, a small molecule inhibitor of CSF‐1R, enhanced the chemotherapeutic effects, inhibiting neuroblastoma growth and improving survival. The findings could have implications for the treatment of neuroblastoma and other cancers with limited cancer‐fighting T‐lymphocyte responses.