Colony stimulating factor 1 receptor blockade improves the efficacy of chemotherapy against human neuroblastoma in the absence of T lymphocytes

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.

Monitoring Immune Responses in Neuroblastoma Patients during Therapy

“…No studies have monitored immune markers in the TME during chemotherapy in patients. An in vivo mouse study showed that depletion of TAMs from NBL tumors is associated with increased chemotherapeutic efficacy without requiring T cell contribution [56]. This observation led to the author's suggestion to combine CSF-1R blockade with chemotherapy to potentially increase treatment efficacy.…”

Zebrafish macrophage developmental arrest underlies depletion of microglia and reveals Csf1r-independent metaphocytes

“…Detailed analysis of the Csf1r mutant phenotypes could therefore contribute to the identification of specific and universal features of organism-wide macrophage development. In addition, it is important to understand the systemic effects of CSF1R inhibition on macrophages, as inhibition of CSF1R is a clinical strategy for the intentional depletion of macrophages in various disease contexts, including Alzheimer’s disease, brain injury and cancer (Edwards et al, 2019; Lloyd et al, 2019; Tap et al, 2015; Webb et al, 2018).…”

Detection of CSF1 rearrangements deleting the 3′ UTR in tenosynovial giant cell tumors

“…The presence of dysregulation of CSF1‐CSF1R (a.k.a. macrophage colony‐stimulating factor receptor, the product of the c‐fms protooncogene) signaling has inspired the clinical use of receptor‐tyrosine kinase inhibition to treat tenosynovial giant cell tumors, and prompted clinical trials of selective CSF1 and CSF1‐receptor inhibitors that have shown promising activity as a targeted therapy for this disease (eg, NCT01643850, http://clinicaltrials.gov), as well as in other tumors that over‐express CSF1 …”

“…gov), [9][10][11][12] as well as in other tumors that over-express CSF1. 13 While the most common CSF1 fusion partner has been reported to be COL6A3, identified in 33% of cases, and thought to result in overexpression of full-length CSF1 via promoter swapping, 7 others have reported that the CSF1 breakpoint was downstream of exon 5, and led to the replacement (by alternate sequences) of the 3 0 untranslated region (UTR) in an otherwise intact CSF1. [14][15][16] Thus, it has been proposed that truncation of this region may account for CSF1 overexpression in some cases of tenosynovial giant cell tumor.…”