3.2.3　Bone Marrow-Derived Cells

These cells represent a heterogeneous population of cells of myeloid origin consisting of myeloid progenitors and immature macrophages, granulocytes and dendritic cells providing a quiescent microenvironment for stem cells maintenance.During the tumorigenesis process, the growth factors released by the tumor induce a switch from a quiescent state to a highly pro-tumorigenic environment.The BM-derived cells involved in tumorigenesis are TAMs, MDSCs, mesenchymal stem cells (MSCs), EPCs, Tie2-expressing monocytes (TEMs), mast cells, neutrophils, pericytes, T cells, NK cells, and hemangiocytes.These cells are involved in activation of angiogenesis, blood vessel stabilization and immune response suppression by suppressing T-cell activation, increasing of neutrophils recruitment with subsequent enhancement in angiogenesis and TAM activation.The most prominent cells recruited into the tumor in response to gradient of soluble chemokine are TAMs that after activation acquires two different phenotypes: M1 generating the host response against the tumor and M2 promoting tumor growth by cytokine production enhancing angiogenesis,metastasis and immune suppression.Expression of glycoprotein colony stimulating factor-1 receptor (CSF-1R), also known as macrophage-CSF (M-CSF) on TAM and high colony stimulating factor-1 (CSF-1) levels correlate with poor prognosis in different solid tumors.The interaction between CSF-1R and CSF-1 is crucial for differentiation and proliferation of M2 macrophages promoting tumor growth, matrix remodeling, angiogenesis, chemotactic motility of tumor cells favoring metastasis.TAMs play different roles in cancer development by producing several cytokines such as IL-6/IL-17/IL-23 or mitogens that via STAT3 signaling pathway in tumor cell initiate and promote tumor process.These cells also regulate angiogenesis by producing VEGF,TNF-α, IL-1β, IL-8 (CXCL8), PDGF, FGF, thymidine phosphorylase, MMPs, and other molecules that are involved in tumor angiogenesis and blood vessel stabilization.Additionally, they activate osteoclast proliferation with consequent increase of bone resorption process.TAMs have also immunoregulatory activity because they produce IL-10 inducing the expression of PD-L1 on monocytes inhibiting CD8+ cell response.They produce prostaglandin E2 (PGE2), IL-10 and indoleamine 2,3-dioxygenase responsible for induction of Tregs, other than production of CCL17,CCL18, and CCL22 representing chemotactic factors for Tregs with subsequent suppression of T cell in TME.Other than immunomodulatory activity, these cells play a role in metastatization of tumor cells.TAMs, in fact, produce proteases including cathepsin B, MMP2, MMP7, and MMP9 cleaving the ECM and thereby providing conduits for tumor cells.These cells play a role in the formation of premetastatic niches because they produce TNF-α, VEGF, TGF-β that through the blood system arrive to other tissues where they recruit macrophages and tumor cells promoting the formation of metastatic foci [32, 42].(https://www.daowen.com)

Monoclonal antibodies and small molecules targeted against CSF-1R and CSF are under evaluation in clinical trials as single agent or in combination therapy.Pexidartinib (PLX3397), ARRY-382,PLX7486, BLZ945, JNJ-40346527 are targeted against CSF-1R intracellular tyrosine kinase domain.These drugs are under evaluation as monotherapy in different solid tumors in phase I and II studies.Preliminary results reported for Pexidartinib and JNJ-40346527 show an objective response rate (ORR) of 5% in classical Hodgkin lymphoma (NCT01217229 and NCT01572519).Emactuzumab, AMG820, IMC-CS4 and MSC110 are monoclonal antibodies tested against solid tumor as single agents.In phase I study Emactuzumab showed partial metabolic response in 11% of patients with solid tumors (NCT01494688) with a significant reduction of TAM on tumor biopsies performed at baseline compared to on-treatment.Several studies with IMC-CS4 in solid tumors(NCT01346358), in breast cancer and prostate cancer (NCT02235536) are ongoing.A rare disease in which CSF-1R/CSF1 pathway is overexpressed is diffuse-type tenosynovial giant cell tumors(dt-GCT) characterized by an important tumor infiltration from CSF-1R macrophages and characterized by 1p13 chromosomal translocation containing CSF1 gene.A phase I study with emactuzumab conducted on 28 patients affected by dt-GCT showed a remarkable activity with 79%of patients showing partial response, 7% complete response and these responses were durable (＞1.9 years).Another study evaluating pexidartinib in dt-GCT showed a partial response in 52% of patients, 30% stable disease and these responses were also durable in this study.A phase 3 study is ongoing in patients with dt-GCT or giant cell tumors of the tendon sheath (GCT-TS) with pexidartinib versus placebo (NCT02371369).Combination therapy with CSF-1R inhibitors and chemotherapy, radiotherapy, immunotherapy is ongoing based on preclinical studies showing that CSF-1/CSF-1R signaling blockade can reduce T cell suppressive TAM infiltration and modulate tumor microenvironment.Pexidartinib is under evaluation in phase 1 and phase 1/2 trial in combination with radiotherapy and androgen deprivation in prostate cancer (NCT02472275), with chemotherapy (NCT01525602 and NCT0159675) or immunotherapy (NCT02452424 and NCT02777710) in solid tumors.Emactuzumab is under evaluation in a phase II study(NCT02923739) assessing its efficacy following paclitaxel and bevacizumab in patients with platinum-resistant, epithelial ovarian, fallopian tube or primary peritoneal cancer.Combination of emactuzumab and atezolizumab in solid tumors is ongoing (NCT02323191) [32, 43, 44].