Myeloid-derived suppressor cells (MDSCs) are pathologically activated neutrophils and monocytes with potent immunosuppressive activity. They are implicated in the regulation of immune responses in ...many pathological conditions and are closely associated with poor clinical outcomes in cancer. Recent studies have indicated key distinctions between MDSCs and classical neutrophils and monocytes, and, in this Review, we discuss new data on the major genomic and metabolic characteristics of MDSCs. We explain how these characteristics shape MDSC function and could facilitate therapeutic targeting of these cells, particularly in cancer and in autoimmune diseases. Additionally, we briefly discuss emerging data on MDSC involvement in pregnancy, neonatal biology and COVID-19.
Immunotherapy has revolutionized the treatment of cancer patients. Among immunotherapeutic approaches, antibodies targeting immune checkpoint inhibitors Programmed cell death protein 1 (PD-1) and ...cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are approved for treatment of metastatic melanoma and are in clinical trials for a variety of other cancers. The contribution of Natural Killer (NK) cells to the efficacy of immune checkpoint inhibitors is becoming more evident. Enhancing both T and NK cell function in cancer could result in a robust and durable response. Along with the ability to directly kill tumor cells, NK cells can mediate antibody-dependent cellular cytotoxicity (ADCC) given the expression of Fragment Crystallizable (Fc) receptors. Promising novel antibodies modified with improved Fc-receptor-mediated functions or Fc-engagers to kill target cells have been tested in pre-clinical models with considerable results. Combination therapies with immune-therapeutic antibodies with enhancers of NK-cell Fc-receptor-mediated function can be exploited to increase the efficacy of these antibodies. Herein, I discuss possible strategies to improve the success of immunotherapy by boosting NK cell function.
Myeloid-derived suppressor cells (MDSC) are pathologically activated neutrophils and monocytes with potent immune suppressive activity. These cells play an important role in accelerating tumor ...progression and undermining the efficacy of anti-cancer therapies. The natural mechanisms limiting MDSC activity are not well understood. Here, we present evidence that type I interferons (IFN1) receptor signaling serves as a universal mechanism that restricts acquisition of suppressive activity by these cells. Downregulation of the IFNAR1 chain of this receptor is found in MDSC from cancer patients and mouse tumor models. The decrease in IFNAR1 depends on the activation of the p38 protein kinase and is required for activation of the immune suppressive phenotype. Whereas deletion of IFNAR1 is not sufficient to convert neutrophils and monocytes to MDSC, genetic stabilization of IFNAR1 in tumor bearing mice undermines suppressive activity of MDSC and has potent antitumor effect. Stabilizing IFNAR1 using inhibitor of p38 combined with the interferon induction therapy elicits a robust anti-tumor effect. Thus, negative regulatory mechanisms of MDSC function can be exploited therapeutically.
Several immune cell populations are involved in cartilage damage, bone erosion, and resorption processes during osteoarthritis. The purpose of this study was to investigate the role of NK cells in ...the pathogenesis of experimental osteoarthritis and whether and how neutrophils can regulate their synovial localization in the disease. Experimental osteoarthritis was elicited by intra-articular injection of collagenase in wild type and
8-wk old mice. To follow osteoarthritis progression, cartilage damage, synovial thickening, and osteophyte formation were measured histologically. To characterize the inflammatory cells involved in osteoarthritis, synovial fluid was collected early after disease induction, and the cellular and cytokine content were quantified by flow cytometry and ELISA, respectively. We found that NK cells and neutrophils are among the first cells that accumulate in the synovium during osteoarthritis, both exerting a pathogenic role. Moreover, we uncovered a crucial role of the CXCL10/CXCR3 axis, with CXCL10 increasing in synovial fluids after injury and
mice being protected from disease development. Finally, in vivo depletion experiments showed that neutrophils are involved in an NK cell increase in the synovium, possibly by expressing CXCL10 in inflamed joints. Thus, neutrophils and NK cells act as important disease-promoting immune cells in experimental osteoarthritis and their functional interaction is promoted by the CXCL10/CXCR3 axis.
Natural killer (NK) cells are key innate immune effectors against multiple myeloma, their activity declining in multiple myeloma patients with disease progression. To identify the mechanisms ...underlying NK cell functional impairment, we characterized the distribution of functionally distinct NK cell subsets in the bone marrow of multiple myeloma-bearing mice. Herein we report that the number of KLRG1(-) NK cells endowed with potent effector function rapidly and selectively decreases in bone marrow during multiple myeloma growth, this correlating with decreased bone marrow NK cell degranulation in vivo. Altered NK cell subset distribution was dependent on skewed chemokine/chemokine receptor axes in the multiple myeloma microenvironment, with rapid downmodulation of the chemokine receptor CXCR3 on NK cells, increased CXCL9 and CXCL10, and decreased CXCL12 expression in bone marrow. Similar alterations in chemokine receptor/chemokine axes were observed in patients with multiple myeloma. Adoptive transfer experiments demonstrated that KLRG1(-) NK cell migration to the bone marrow was more efficient in healthy than multiple myeloma-bearing mice. Furthermore, bone marrow localization of transferred CXCR3-deficient NK cells with respect to wild type was enhanced in healthy and multiple myeloma-bearing mice, suggesting that CXCR3 restrains bone marrow NK cell trafficking. Our results indicate that multiple myeloma-promoted CXCR3 ligand upregulation together with CXCL12 downmodulation act as exit signals driving effector NK cells outside the bone marrow, thus weakening the antitumor immune response at the primary site of tumor growth.
The protein chaperone HSP70 is overexpressed in many cancers including colorectal cancer, where overexpression is associated with poor survival. We report here the creation of a uniquely acting HSP70 ...inhibitor (HSP70i) that targets multiple compartments in the cancer cell, including mitochondria. This inhibitor was mitochondria toxic and cytotoxic to colorectal cancer cells, but not to normal colon epithelial cells. Inhibition of HSP70 was efficacious as a single agent in primary and metastatic models of colorectal cancer and enabled identification of novel mitochondrial client proteins for HSP70. In a syngeneic colorectal cancer model, the inhibitor increased immune cell recruitment into tumors. Cells treated with the inhibitor secreted danger-associated molecular patterns (DAMP), including ATP and HMGB1, and functioned effectively as a tumor vaccine. Interestingly, the unique properties of this HSP70i in the disruption of mitochondrial function and the inhibition of proteostasis both contributed to DAMP release. This HSP70i constitutes a promising therapeutic opportunity in colorectal cancer and may exhibit antitumor activity against other tumor types. SIGNIFICANCE: These findings describe a novel HSP70i that disrupts mitochondrial proteostasis, demonstrating single-agent efficacy that induces immunogenic cell death in treated tumors.
BackgroundCeralasertib is a specific ATR inhibitor (ATRi) that hinders the DNA damage response in tumor cells, making them more susceptible to death in situations of high replication stress. ...Ceralasertib in combination with the PD-L1 antibody durvalumab demonstrated encouraging clinical benefit in melanoma and lung cancer patients who progressed on immunotherapy. The mechanism of this effect remained unclear.MethodsIn this study, we employed different mouse tumor models treated with ceralasertib to investigate the effect of the ATRi on tumor microenvironment.ResultsAntitumor effect of ceralasertib was dependent on the presence of CD8 cells, since in vivo depletion of CD8 cells abrogated therapeutic effect of the ATRi. Analysis of the gene expression profile using RNAseq demonstrated significant up-regulation of type I interferon (IFNI) pathway in tumors of mice treated with ceralasertib. Neutralizing anti IFNI receptor (IFNAR1) antibody abrogated antitumor effect of ceralasertib. Antitumor effect of ceralasertib in combination with anti-PD-L1 was eliminated in mice reconstituted with bone marrow from IFNAR1-KO mice. Reconstitution with bone marrow from mice with constitutively active IFNAR1 markedly enhanced antitumor effect of ceralasertib. Treatment of tumor-bearing mice with ceralasertib caused accumulation of DCs with activated phenotype (up-regulation of CD40, CD86, MHC class II). DCs isolated from tumor of ceralasertib-treated mice demonstrated an enhanced ability to stimulate T cells in a mixed lymphocyte reaction assay. Notably, this effect was reversed when DCs were isolated from IFNAR1 KO mice. Moreover, in vitro-generated DCs treated with ceralasertib exhibited activation similar to that induced by lipopolysaccharide (LPS), but this effect was not observed in DCs generated from IFNAR1 KO mice. Treatment with ceralasertib led to the depletion in tumor of M-MDSC and TAMs, but not PMN-MDSC. However, PMN-MDSCs suppressive activity was abrogated after the treatment. This was associated with increased IFNI signature observed in tumor PMN-MDSC. Treatment with ceralasertib enhanced tumor antigen-specific response of T cells.ConclusionsOur findings demonstrate IFNI mediated modulation of TME by ceralasertib resulting in enhanced antitumor activity of T cells and potentiated effect of PD-L1 antibody.
Myeloid-derived suppressor cells (MDSC) are important regulators of immune responses in cancer. They represent a relatively stable form of pathologic activation of neutrophils and monocytes and are ...characterized by distinct transcriptional, biochemical, functional, and phenotypical features. The close association of MDSCs with clinical outcomes in cancer suggests that these cells can be an attractive target for therapeutic intervention. However, the complex nature of MDSC biology represents a substantial challenge for the development of selective therapies. Here, we discuss the mechanisms regulating MDSC development and fate and recent research advances that have demonstrated opportunities for therapeutic regulation of these cells. SIGNIFICANCE: MDSCs are attractive therapeutic targets because of their close association with negative clinical outcomes in cancer and established biology as potent immunosuppressive cells. However, the complex nature of MDSC biology presents a substantial challenge for therapeutic targeting. In this review, we discuss those challenges and possible solutions.
In this study, using single-cell RNA-seq, cell mass spectrometry, flow cytometry, and functional analysis, we characterized the heterogeneity of polymorphonuclear neutrophils (PMNs) in cancer. We ...describe three populations of PMNs in tumor-bearing mice: classical PMNs, polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), and activated PMN-MDSCs with potent immune suppressive activity. In spleens of mice, PMN-MDSCs gradually replaced PMNs during tumor progression. Activated PMN-MDSCs were found only in tumors, where they were present at the very early stages of the disease. These populations of PMNs in mice could be separated based on the expression of CD14. In peripheral blood of cancer patients, we identified two distinct populations of PMNs with characteristics of classical PMNs and PMN-MDSCs. The gene signature of tumor PMN-MDSCs was similar to that in mouse activated PMN-MDSCs and was closely associated with negative clinical outcome in cancer patients. Thus, we provide evidence that PMN-MDSCs are a distinct population of PMNs with unique features and potential for selective targeting opportunities.
Myeloid-derived suppressor cells (MDSC) are immunosuppressive myeloid cells that accumulate in tumor sites and peripheral lymphoid organs such as the spleen. In murine cancer models, the spleen is a ...major reservoir for MDSC, representing an easily accessible tissue from which to isolate high numbers of these cell population for downstream applications. Here we describe an efficient method to phenotype as well as to isolate and assess the functionality of murine splenic MDSC.
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