Various steady state and inflamed tissues have been shown to contain a heterogeneous DC population consisting of developmentally distinct subsets, including cDC1s, cDC2s and monocyte-derived DCs, displaying differential functional specializations. The identification of functionally distinct tumour-associated DC (TADC) subpopulations could prove essential for the understanding of basic TADC biology and for envisaging targeted immunotherapies. We demonstrate that multiple mouse tumours as well as human tumours harbour ontogenically discrete TADC subsets. Monocyte-derived TADCs are prominent in tumour antigen uptake, but lack strong T-cell stimulatory capacity due to NO-mediated immunosuppression. Pre-cDC-derived TADCs have lymph node migratory potential, whereby cDC1s efficiently activate CD8+ T cells and cDC2s induce Th17 cells. Mice vaccinated with cDC2s displayed a reduced tumour growth accompanied by a reprogramming of pro-tumoural TAMs and a reduction of MDSCs, while cDC1 vaccination strongly induces anti-tumour CTLs. Our data might prove important for therapeutic interventions targeted at specific TADC subsets or their precursors.

Tumors contain a heterogeneous myeloid fraction comprised of discrete MHC-II hi and MHC-II lo tumor-associated macrophage (TAM) subpopulations that originate from Ly6C hi monocytes. However, the mechanisms regulating the abundance and phenotype of distinct TAM subsets remain unknown. Here, we investigated the role of macrophage colony-stimulating factor (M-CSF) in TAM differentiation and polarization in different mouse tumor models. We demonstrate that treatment of tumor-bearing mice with a blocking anti-M-CSFR monoclonal antibody resulted in a reduction of mature TAMs due to impaired recruitment, extravasation, proliferation, and maturation of their Ly6C hi monocytic precursors. M-CSFR signaling blockade shifted the MHC-II lo / MHC-II hi TAM balance in favor of the latter as observed by the preferential differentiation of Ly6C hi monocytes into MHC-II hi TAMs. In addition, the genetic and functional signatures of MHC-II lo TAMs were downregulated upon M-CSFR blockade, indicating that M-CSFR signaling shapes the MHC-II lo TAM phenotype. Conversely, granulocyte macrophage (GM)-CSFR had no effect on the mononuclear tumor infiltrate or relative abundance of TAM subsets. However, GM-CSFR signaling played an important role in fine-tuning the MHC-II hi phenotype. Overall, our data uncover the multifaceted and opposing roles of M-CSFR and GM-CSFR signaling in governing the phenotype of macrophage subsets in tumors, and provide new insight into the mechanism of action underlying M-CSFR blockade. Cancer Res; 76(1); 35-42. Ó2015 AACR.

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Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells that accumulate during pathological conditions such as cancer and are associated with a poor clinical outcome. MDSC expansion hampers the host anti-tumor immune response by inhibition of T cell proliferation, cytokine secretion, and recruitment of regulatory T cells. In addition, MDSC exert non-immunological functions including the promotion of angiogenesis, tumor invasion, and metastasis. Recent years, MDSC are considered as a potential target in solid tumors and hematological malignancies to enhance the effects of currently used immune modulating agents. This review focuses on the characteristics, distribution, functions, cell–cell interactions, and targeting of MDSC in hematological malignancies including multiple myeloma, lymphoma, and leukemia.

The tumor stroma has long been ignored as therapeutic target, but it has become clear that several stromal cell types play a nonredundant role during tumor progression. In particular, macrophages possess the capacity to stimulate tumor growth and metastasis via multiple mechanisms. [3]). Only upon experimentally re-educating TAMs, through the blockade of phagocytosis-inhibiting molecules such as CD47 [4], the provision of cytotoxicity-stimulating triggers such as CD40 and/or TLR ligands [5], the provision of macrophage repolarizing molecules such as histidine-rich glycoprotein [6], or the prevention of TAM migration to hypoxic areas [7], do these cells acquire antitumoral activity. In this respect, distinct TAM subpopulations exist within the same tumor-as demonstrated by earlier studies [8][9][10] and by Tymoszuk et al. in this issue of the European Journal of Immunology [11]-which might perform distinct functions. Hence, the ablation of tumor-promoting cells while leaving antitumoral populations unharmed could be envisaged as an anticancer strategy. Alternatively, preventing the establishment of the TAM pool could be another valid therapeutic strategy, but requires a better insight into the mechanisms governing the TAM pool size. Monocyte recruitment to the tissue and their differentiation into macrophages has long been known to supply sufficient amounts of phagocytes during inflammation, but more recently the importance of local macrophage proliferation at the site of inflammation has been underscored (reviewed in [12]). Tymoszuk et al.[11] demonstrate the contribution of both phenomena to TAM populations in the MMTV-Neu mouse model of oncogene-driven mammary carcinogenesis (Fig. 1) promoter contains four putative STAT1-binding GAS (interferongamma-activated sequences) elements, of which at least GAS1 binds STAT1 in response to IFN-γ treatment of cancer cells [11]. Importantly, the GAS1 sequence is conserved across mammalian species, including humans. CSF-1 drives hematopoietic stem cells toward the myeloid lineage and remains an important growth factor for the generation of monocytes and macrophages [21]. In reorganizing tissues-as a consequence of inflammation, wound healing or nonpathological events such as pregnancy-CSF-1 has been reported to regulate monocyte and macrophage dynamics. For example, in the myometrium of the pregnant uterus, CSF-1 regulates the macrophage pool by strongly increasing the extravasation of Ly6C hi monocytes and boosting local macrophage prolifera- Overall, the new information reported in the study by Tymoszuk et al. [11] provides further evidence for the existence of at least two main TAM subsets in tumors and identifies monocyte attraction and in situ macrophage proliferation as parallel mechanisms determining the TAM pool size. These data imply that antiproliferative agents currently in use as cancer therapeutics not only target cancer cells but might also hamper TAM functionality. CSF-1R signaling is instrumental in this scenario and constitutes a valid therapeutic target. ...

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<p>Description of additional methods and procedures used in the study.</p>

<p>Effects of α-M-CSFR Ab treatment on Ly6Chi monocyte function (S1); Effect of M-CSFR blockade on the survival of Ly6Chi monocytes and TAM (S2); Effect of M-CSFR blockade on Ly6Chi monocyte percentages in peripheral blood, spleen and bone marrow (S3); Absolute numbers of myeloid cell subsets in tumors from isotype or α-M-CSFR Ab-treated animals (S4); Production of M-CSF, IL-34 and GM-CSF by 3LL-R tumors (S5); Effect of M-CSFR blockade on monocyte differentiation in TS/A breast carcinoma tumors (S6); M-CSFR-mediated regulation of gene expression is IL-4Rα- independent (S7); Mixed Leukocyte Reaction (MLR) by TAM subsets from isotype or α-M-CSFR Ab treated animals (S8); M-CSFR blockade enhanced the M1-like MHC-IIhi TAM gene signature independently of GM-CSFR signaling (S9).</p>