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  • Currently multiple clinical trials of CSF CSF R targeting ag

    2021-02-25

    Currently, multiple clinical trials of CSF-1/CSF-1R-targeting agents in combination with standard treatment modalities and immunotherapies are underway (Table 1). In particular, results for combinations with checkpoint blockade inhibitors and other immunotherapeutic approaches are eagerly awaited.
    Till date, most of the data on TAM and other myeloid cell populations derive from transplanted syngeneic (or even xenograft) tumor models or oncogene driven tumors, not reflecting the high TAM heterogeneity in human patients. Unlike other immune Cy3 carboxylic acid (non-sulfonated) sale relevant for cancer immunotherapy such as T cells, which express defined marker sets to describe different subtypes, macrophage populations shift expression of multiple markers upon activation leading to unclear, often confusing nomenclature and differentiation/characterization protocols in vitro and ex vivo. Hence, many renowned macrophage experts recently convened and proposed uniform guidelines on nomenclature and experimental standards for human and mouse macrophages []. The detailed profiling of human macrophages is hampered by poor accessibility to sufficient numbers of tissue-derived macrophages as opposed to in vitro differentiated macrophages. One of the few exemplary studies was performed by Cavnar, who functionally characterized TAM isolated from gastrointestinal stromal tumor patients, revealing a switch from M1- to M2-like phenotype induced by imatinib therapy []. The team of Biswas sought to elucidate the tumor-mediated control mechanisms of macrophage activation by analyzing monocytes isolated from renal cell carcinoma (RCC) patients and compared gene expression profiles to monocytes of healthy donors []. The RCC monocytes were characterized by the expression of pro-inflammatory genes such as TNFα, IL-1β, as well as pro-tumoral genes e.g. VEGF-A, IL-8 and matrix metalloproteases. Finally, signaling via IL-1/IL-1R was found to drive the resulting macrophage population into a pro-tumoral phenotype with respect to their pro-angiogenic function in vitro and the tumor supporting role studied in a xenograft model []. Martinez directly compared gene and protein expression of mouse and human macrophages and identified a common signature of 87 genes that was further validated in biopsies of human lung tissue []. Interestingly, this signature did not include CSF-1R or CD68 due to the bias toward high level of gene expression applied for defining the signature []. However, to fully understand if and how in vitro differentiated macrophages/myeloid cells from peripheral blood monocytes of healthy donors may represent tumor-associated myeloid phenotypes and function demands more systematic analysis. Another fundamental question is, whether tissue macrophages and, in particular, TAMs originate from circulating monocytes. A contribution of yolk sac, fetal liver, bone marrow and spleen in generating macrophage precursors in mice has been described [10]. Comparing murine gene signatures, Hashimoto and colleagues proposed that murine monocytes and tissue macrophages (lung, spleen, peritoneum or bone marrow) are to be regarded as myeloid cells with independent steady state maintenance [25]. In contrast, data from CCR2−/−PyMT and CCR2DTR-PyMT breast cancer models indicate that mammary tissue macrophages and, to a lesser extent, TAM are constitutively repopulated by circulating monocytes [26]. Conversely, Caescu reported that CSF-1 supports polarization toward a pro-tumorigenic M2 phenotype via microRNA-21 by decreasing pro-inflammatory molecules together with up-regulation of M2-marker expression [27], whereas microRNA-511-3p limits the pro-tumoral function of TAM [28]. Overall, the origin and phenotype of TAM in patients requires in depth analysis and a systematic comparison to the respective mouse models. Macrophage signatures from in vitro differentiated monocytes should be regarded as extremes generated under very stringent conditions. This makes comparative data analysis and interpretation challenging as the myeloid cells adapt to minimal changes of micro-environmental stimuli with distinct gene expression signatures [29].