Monocytes and their tissue counterpart macrophages (MP) constitute the front line of the immune system. Indeed, they are able to rapidly and efficiently detect both external and internal danger ...signals, thereby activating the immune system to eradicate the disturbing biological, chemical, or physical agents. They are also in charge of the control of the immune response and account for the repair of the damaged tissues, eventually restoring tissue homeostasis. The balance between these dual activities must be thoroughly controlled in space and time. Any sustained unbalanced response of MP leads to pathological disorders, such as chronic inflammation, or favors cancer development and progression. In this review, we take advantage of our expertise in chronic inflammation, especially in rheumatoid arthritis, and in cancer, to highlight the pivotal role of MP in the physiopathology of these disorders and to emphasize the repolarization of unbalanced MP as a promising therapeutic strategy to control these diseases.
Interleukin-33 (IL-33), considered as an alarmin released upon tissue stress or damage, is a member of the IL-1 family and binds the ST2 receptor. First described as a potent initiator of type 2 ...immune responses through the activation of T helper 2 (T
2) cells and mast cells, IL-33 is now also known as an effective stimulator of T
1 immune cells, natural killer (NK) cells, iNKT cells, and CD8 T lymphocytes. Moreover, IL-33 was shown to play an important role in several cancers due to its pro and anti-tumorigenic functions. Currently, IL-33 is a possible inducer and prognostic marker of cancer development with a direct effect on tumor cells promoting tumorigenesis, proliferation, survival, and metastasis. IL-33 also promotes tumor growth and metastasis by remodeling the tumor microenvironment (TME) and inducing angiogenesis. IL-33 favors tumor progression through the immune system by inducing M2 macrophage polarization and tumor infiltration, and upon activation of immunosuppressive cells such as myeloid-derived suppressor cells (MDSC) or regulatory T cells. The anti-tumor functions of IL-33 also depend on infiltrated immune cells displaying T
1 responses. This review therefore summarizes the dual role of this cytokine in cancer and suggests that new proposals for IL-33-based cancer immunotherapies should be considered with caution.
Dendrimers are well-defined macromolecules whose highly branched structure is reminiscent of many natural structures, such as trees, dendritic cells, neurons or the networks of kidneys and lungs. ...Nature has privileged such branched structures for increasing the efficiency of exchanges with the external medium; thus, the whole structure is of pivotal importance for these natural networks. On the contrary, it is generally believed that the properties of dendrimers are essentially related to their terminal groups, and that the internal structure plays the minor role of an 'innocent' scaffold. Here we show that such an assertion is misleading, using convergent information from biological data (human monocytes activation) and all-atom molecular dynamics simulations on seven families of dendrimers (13 compounds) that we have synthesized, possessing identical terminal groups, but different internal structures. This work demonstrates that the scaffold of nanodrugs strongly influences their properties, somewhat reminiscent of the backbone of proteins.
Cancer remains a leading cause of death in the world. To overcome this problem, it is necessary to develop new analysis tools, in complementarity to existing ones, to enable the early diagnostic of ...the diseases, personalized treatment, and further fundamental cancer mechanisms understanding. In this context, microwave-based and millimeter-wave-based dielectric spectroscopy performed at the cellular and molecular levels is progressively emerging, as it permits the non-invasive and real-time probing of cells in their culture biological medium. The recent advances of this topic are given in this paper with a specific highlight of its various assets.
Abstract Human natural killer (NK) cells play a key role in anti-cancer and anti-viral immunity, but their selective amplification in vitro is extremely tedious to achieve and remains one of the most ...challenging problems to solve for efficient NK cell-based immuno-therapeutic treatments against malignant diseases. Here we report that, when added to ex vivo culture of peripheral blood mononuclear cells from healthy volunteers or from cancer patients with multiple myeloma, poly (phosphorhydrazone) dendrimers capped with amino-bis(methylene phosphonate) end groups enable the efficient proliferation of NK cells with anti-cancer cytotoxicity in vivo . We also show that the amplification of the NK population relies on the preliminary activation of monocytes in the framework of a multistep cross-talk between monocytes and NK cells before the proliferation thereof. Thus poly(phosphorhydrazone) dendrimers represent a novel class of extremely promising drugs to develop NK-cell based anti-cancer therapies.
Most human blood γδ cells are cytolytic TCRVγ9Vδ2
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lymphocytes with antitumor activity. They are currently investigated in several clinical trials of cancer immunotherapy but so far, their tumor ...infiltration has not been systematically explored across human cancers. Novel algorithms allowing the deconvolution of bulk tumor transcriptomes to find the relative proportions of infiltrating leucocytes, such as CIBERSORT, should be appropriate for this aim but in practice they fail to accurately recognize γδ T lymphocytes. Here, by implementing machine learning from microarray data, we first improved the computational identification of blood-derived TCRVγ9Vδ2
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γδ lymphocytes and then applied this strategy to assess their abundance as tumor infiltrating lymphocytes (γδ TIL) in ∼10,000 cancer biopsies from 50 types of hematological and solid malignancies. We observed considerable inter-individual variation of TCRVγ9Vδ2
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γδ TIL abundance both within each type and across the spectrum of cancers tested. We report their prominence in B cell-acute lymphoblastic leukemia (B-ALL), acute promyelocytic leukemia (M3-AML) and chronic myeloid leukemia (CML) as well as in inflammatory breast, prostate, esophagus, pancreas and lung carcinoma. Across all cancers, the abundance of αβ TILs and TCRVγ9Vδ2
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γδ TILs did not correlate. αβ TIL abundance paralleled the mutational load of tumors and positively correlated with inflammation, infiltration of monocytes, macrophages and dendritic cells (DC), antigen processing and presentation, and cytolytic activity, in line with an association with a favorable outcome. In contrast, the abundance of TCRVγ9Vδ2
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γδ TILs did not correlate with these hallmarks and was variably associated with outcome, suggesting that distinct contexts underlie TCRVγ9Vδ2
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γδ TIL and αβ TIL mobilizations in cancer.
Despite the advancements in therapy for B cell malignancies and the increase in long-term survival of patients, almost half of them lead to relapse. Combinations of chemotherapy and monoclonal ...antibodies such as anti-CD20 leads to mixed outcomes. Recent developments in immune cell-based therapies are showing many encouraging results. γδ T cells, with their potential of functional plasticity and their anti-tumoral properties, emerged as good candidates for cancer immunotherapies. The representation and the diversity of γδ T cells in tissues and in the blood, in physiological conditions or in B-cell malignancies such as B cell lymphoma, chronic lymphoblastic leukemia or multiple myeloma, provides the possibility to manipulate them with immunotherapeutic approaches for these patients. In this review, we summarized several strategies based on the activation and tumor-targeting of γδ T cells, optimization of expansion protocols, and development of gene-modified γδ T cells, using combinations of antibodies and therapeutic drugs and adoptive cell therapy with autologous or allogenic γδ T cells following potential genetic modifications.
The tumor bulk is composed of a highly heterogeneous population of cancer cells, as well as a large variety of resident and infiltrating host cells, extracellular matrix proteins, and secreted ...proteins, collectively known as the tumor microenvironment (TME). The TME is essential for driving tumor development by promoting cancer cell survival, migration, metastasis, chemoresistance, and the ability to evade the immune system responses. Therapeutically targeting tumor-associated macrophages (TAMs), cancer-associated fibroblasts (CAFs), regulatory T-cells (T-regs), and mesenchymal stromal/stem cells (MSCs) is likely to have an impact in cancer treatment. In this review, we focus on describing the normal physiological functions of each of these cell types and their behavior in the cancer setting. Relying on the specific surface markers and secreted molecules in this context, we review the potential targeting of these cells inducing their depletion, reprogramming, or differentiation, or inhibiting their pro-tumor functions or recruitment. Different approaches were developed for this targeting, namely, immunotherapies, vaccines, small interfering RNA, or small molecules.
The monocyte‐macrophage (MΦ) lineage can undergo different pathways of activation. The classical priming by IFN‐γ, then triggering by LPS, conducts MΦ toward proinflammatory responses, whereas the ...alternative activation by IL‐4, IL‐10, IL‐13, or glucocorticoids directs them toward an anti‐inflammatory, immunosuppressive phenotype. Recently, we have shown that synthetic phosphorus‐containing dendrimers activate human monocytes. Here, we analyzed the gene expression of monocytes activated by an acid azabisphosphonic‐capped, phosphorus‐containing dendrimer by comparison with untreated monocytes. We found that 78 genes were up‐regulated, whereas 62 genes were down‐regulated. Analysis of these genes directed the hypothesis of an alternative‐like, anti‐inflammatory activation of human monocytes. This was confirmed by quantitative RT‐PCR and analysis of the surface expression of specific markers by flow cytometry. Functional experiments of inhibition of CD4+ T‐lymphocyte proliferation in MLR indicated that dendrimer‐activated monocytes (da‐monocytes) have an immune‐suppressive phenotype similar to the one induced by IL‐4. Moreover, da‐monocytes preferentially enhanced amplification of CD4+ T cells, producing IL‐10, an immunosuppressive cytokine. Therefore, phosphorus‐containing dendrimers appear as new nanobiotools promoting an anti‐inflammatory and immunosuppressive activation of human monocytes and thus, prove to be good candidates for innovative, anti‐inflammatory immunotherapies.
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