Persistent Cryptosporidium parvum Infection Leads to the Development of the Tumor Microenvironment in an Experimental Mouse Model: Results of a Microarray Approach

Cryptosporidium spp. are enteric protozoa parasites that infect a variety of vertebrate hosts. These parasites are capable of inducing life-threatening gastrointestinal disease in immunocompromised individuals. With the rising epidemiological evidence of the occurrence of Cryptosporidium infections in humans with digestive cancer, the tumorigenic potential of the parasite has been speculated. In this regard, Cryptosporidium parvum has been reported to induce digestive adenocarcinoma in a rodent model of chronic cryptosporidiosis. However, the processes by which the parasite could induce this carcinogenesis are still unknown. Therefore, the transcriptomes of C. parvum infected ileo-cecal regions of mice developing tumors were analyzed in the current study. For the first time, downregulation of the expression of α-defensin, an anti-microbial target of the parasite in response to C. parvum infection was observed in the transformed tissues. This phenomenon has been speculated to be the result of resistance of C. parvum to the host defense through the upregulated expression of interferon γ-stimulated genes. The inflammatory response generated as result of attenuated expression of anti-microbial peptides highlights the role of immune evasion in the C. parvum-induced tumorigenesis. The study has also succeeded in the characterization of the tumor microenvironment (TME) which is characterized by the presence of cancer associated fibroblasts, myeloid-derived suppressor cells, tumor-associated macrophages and extracellular matrix components. Identification of immune suppressor cells and accumulation of pro-inflammatory mediators speculates that chronic inflammation induced by persistent C. parvum infection assists in development of an immunosuppressive tumor microenvironment.

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Overcoming the Immunosuppressive Tumor Microenvironment in Multiple Myeloma

Cancers ◽

10.3390/cancers13092018 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2018

Author(s):

Fatih M. Uckun

Keyword(s):

Multiple Myeloma ◽

T Cell ◽

Tumor Microenvironment ◽

Nk Cell ◽

Suppressor Cells ◽

Alternatively Activated Macrophages ◽

Effector T Cell ◽

Immunosuppressive Tumor Microenvironment ◽

Cytotoxic Effector ◽

Alternatively Activated

SeverFigurel cellular elements of the bone marrow (BM) microenvironment in multiple myeloma (MM) patients contribute to the immune evasion, proliferation, and drug resistance of MM cells, including myeloid-derived suppressor cells (MDSCs), tumor-associated M2-like, “alternatively activated” macrophages, CD38+ regulatory B-cells (Bregs), and regulatory T-cells (Tregs). These immunosuppressive elements in bidirectional and multi-directional crosstalk with each other inhibit both memory and cytotoxic effector T-cell populations as well as natural killer (NK) cells. Immunomodulatory imide drugs (IMiDs), protease inhibitors (PI), monoclonal antibodies (MoAb), adoptive T-cell/NK cell therapy, and inhibitors of anti-apoptotic signaling pathways have emerged as promising therapeutic platforms that can be employed in various combinations as part of a rationally designed immunomodulatory strategy against an immunosuppressive tumor microenvironment (TME) in MM. These platforms provide the foundation for a new therapeutic paradigm for achieving improved survival of high-risk newly diagnosed as well as relapsed/refractory MM patients. Here we review the scientific rationale and clinical proof of concept for each of these platforms.

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Therapeutic Strategies for Overcoming Immunotherapy Resistance Mediated by Immunosuppressive Factors of the Glioblastoma Microenvironment

Cancers ◽

10.3390/cancers12071960 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1960

Author(s):

Tsubasa Miyazaki ◽

Eiichi Ishikawa ◽

Narushi Sugii ◽

Masahide Matsuda

Keyword(s):

Tumor Microenvironment ◽

Immune Checkpoint ◽

Malignant Tumors ◽

Suppressor Cells ◽

Treatment Resistance ◽

Glioma Initiating Cells ◽

Programmed Cell Death 1 ◽

Tumor Immune Microenvironment ◽

Immunosuppressive Tumor Microenvironment ◽

Immunosuppressive Cells

Various mechanisms of treatment resistance have been reported for glioblastoma (GBM) and other tumors. Resistance to immunotherapy in GBM patients may be caused by acquisition of immunosuppressive ability by tumor cells and an altered tumor microenvironment. Although novel strategies using an immune-checkpoint inhibitor (ICI), such as anti-programmed cell death-1 antibody, have been clinically proven to be effective in many types of malignant tumors, such strategies may be insufficient to prevent regrowth in recurrent GBM. The main cause of GBM recurrence may be the existence of an immunosuppressive tumor microenvironment involving immunosuppressive cytokines, extracellular vesicles, chemokines produced by glioma and glioma-initiating cells, immunosuppressive cells, etc. Among these, recent research has paid attention to various immunosuppressive cells—including M2-type macrophages and myeloid-derived suppressor cells—that cause immunosuppression in GBM microenvironments. Here, we review the epidemiological features, tumor immune microenvironment, and associations between the expression of immune checkpoint molecules and the prognosis of GBM. We also reviewed various ongoing or future immunotherapies for GBM. Various strategies, such as a combination of ICI therapies, might overcome these immunosuppressive mechanisms in the GBM microenvironment.

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Systemic but not MDSC-specific IRF4 deficiency promotes an immunosuppressed tumor microenvironment in a murine pancreatic cancer model

Cancer Immunology Immunotherapy ◽

10.1007/s00262-020-02605-9 ◽

2020 ◽

Vol 69 (10) ◽

pp. 2101-2112

Author(s):

Philipp Metzger ◽

Sabrina V. Kirchleitner ◽

Daniel F. R. Boehmer ◽

Christine Hörth ◽

Angelika Eisele ◽

...

Keyword(s):

Pancreatic Cancer ◽

Tumor Microenvironment ◽

Critical Role ◽

Suppressor Cells ◽

Myeloid Cell ◽

Ductal Adenocarcinoma ◽

Gm Csf ◽

Immunosuppressive Tumor Microenvironment ◽

And Function

Abstract Pancreatic ductal adenocarcinoma is characterized by a strong immunosuppressive network with a dense infiltration of myeloid cells including myeloid-derived suppressor cells (MDSC). Two distinct populations of MDSC have been defined: polymorphonuclear MDSC (PMN-MDSC) and monocytic MDSC (M-MDSC). Several factors influence the development and function of MDSC including the transcription factor interferon regulatory factor 4 (IRF4). Here, we show that IRF4 deficiency accelerates tumor growth and reduces survival, accompanied with a dense tumor infiltration with PMN-MDSC and reduced numbers of CD8+ T cells. As IRF4 has been described to modulate myeloid cell development and function, particularly of PMN-MDSC, we analyzed its role using MDSC-specific IRF4 knockout mice with the Ly6G or LysM knock-in allele expressing Cre recombinase and Irf4flox. In GM-CSF-driven bone marrow cultures, IRF4 deficiency increased the frequency of MDSC-like cells with a strong T cell suppressive capacity. Myeloid (LysM)-specific depletion of IRF4 led to increased tumor weight and a moderate splenic M-MDSC expansion in tumor-bearing mice. PMN cell (Ly6G)-specific depletion of IRF4, however, did not influence tumor progression or MDSC accumulation in vivo in accordance with our finding that IRF4 is not expressed in PMN-MDSC. This study demonstrates a critical role of IRF4 in the generation of an immunosuppressive tumor microenvironment in pancreatic cancer, which is independent of IRF4 expression in PMN-MDSC.

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Significance of Immunosuppressive Cells as a Target for Immunotherapies in Melanoma and Non-Melanoma Skin Cancers

Biomolecules ◽

10.3390/biom10081087 ◽

2020 ◽

Vol 10 (8) ◽

pp. 1087 ◽

Cited By ~ 2

Author(s):

Taku Fujimura ◽

Setsuya Aiba

Keyword(s):

T Cells ◽

Tumor Microenvironment ◽

Tumor Cells ◽

Tumor Development ◽

Suppressor Cells ◽

Related Factors ◽

Skin Cancers ◽

Immunosuppressive Tumor Microenvironment ◽

Immunosuppressive Cells ◽

Promote Tumor Development

Tumor-associated macrophages (TAMs) have been detected in most skin cancers. TAMs produce various chemokines and angiogenic factors that promote tumor development, along with other immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and tumor-associated neutrophils. TAMs generated from monocytes develop into functional, fully activated macrophages, and TAMs obtain various immunosuppressive functions to maintain the tumor microenvironment. Since TAMs express PD1 to maintain the immunosuppressive M2 phenotype by PD1/PD-L1 signaling from tumor cells, and the blockade of PD1/PD-L1 signaling by anti-PD1 antibodies (Abs) activate and re-polarize TAMs into immunoreactive M1 phenotypes, TAMs represent a potential target for anti-PD1 Abs. The main population of TAMs comprises CD163+ M2 macrophages, and CD163+ TAMs release soluble (s)CD163 and several proinflammatory chemokines (CXCL5, CXCL10, CCL19, etc.) as a result of TAM activation to induce an immunosuppressive tumor microenvironment together with other immunosuppressive cells. Since direct blockade of PD1/PD-L1 signaling between tumor cells and tumor-infiltrating T cells (both effector T cells and Tregs) is mandatory for inducing an anti-immune response by anti-PD1 Abs, anti-PD1 Abs need to reach the tumor microenvironment to induce anti-immune responses in the tumor-bearing host. Taken together, TAM-related factors could offer a biomarker for anti-PD1 Ab-based immunotherapy. Understanding the crosstalk between TAMs and immunosuppressive cells is important for optimizing PD1 Ab-based immunotherapy.

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VEGF in ovarian cancer suppresses T cell activity by eliciting Myeloid Derived Suppressor Cells (MDSC) into tumor microenvironment

10.26226/morressier.5770e29cd462b80290b4bf91 ◽

2016 ◽

Author(s):

Naoki Horikawa

Keyword(s):

Ovarian Cancer ◽

T Cell ◽

Tumor Microenvironment ◽

Cell Activity ◽

Suppressor Cells ◽

Myeloid Derived Suppressor Cells

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GCN2 drives macrophage and MDSC function and immunosuppression in the tumor microenvironment

Science Immunology ◽

10.1126/sciimmunol.aax8189 ◽

2019 ◽

Vol 4 (42) ◽

pp. eaax8189 ◽

Cited By ~ 7

Author(s):

Marie Jo Halaby ◽

Kebria Hezaveh ◽

Sara Lamorte ◽

M. Teresa Ciudad ◽

Andreas Kloetgen ◽

...

Keyword(s):

Transcription Factor ◽

Macrophage Polarization ◽

Suppressor Cells ◽

Interferon Γ ◽

Mass Cytometry ◽

General Control ◽

Immune Attack ◽

Environmental Sensor ◽

Rna Knockdown ◽

Interfering Rna

General control nonderepressible 2 (GCN2) is an environmental sensor controlling transcription and translation in response to nutrient availability. Although GCN2 is a putative therapeutic target for immuno-oncology, its role in shaping the immune response to tumors is poorly understood. Here, we used mass cytometry, transcriptomics, and transcription factor–binding analysis to determine the functional impact of GCN2 on the myeloid phenotype and immune responses in melanoma. We found that myeloid-lineage deletion of GCN2 drives a shift in the phenotype of tumor-associated macrophages and myeloid-derived suppressor cells (MDSCs) that promotes antitumor immunity. Time-of-flight mass cytometry (CyTOF) and single-cell RNA sequencing showed that this was due to changes in the immune microenvironment with increased proinflammatory activation of macrophages and MDSCs and interferon-γ expression in intratumoral CD8+ T cells. Mechanistically, GCN2 altered myeloid function by promoting increased translation of the transcription factor CREB-2/ATF4, which was required for maturation and polarization of macrophages and MDSCs in both mice and humans, whereas targeting Atf4 by small interfering RNA knockdown reduced tumor growth. Last, analysis of patients with cutaneous melanoma showed that GCN2-dependent transcriptional signatures correlated with macrophage polarization, T cell infiltrates, and overall survival. Thus, these data reveal a previously unknown dependence of tumors on myeloid GCN2 signals for protection from immune attack.

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Melanoma Cell Resistance to Vemurafenib Modifies Inter-Cellular Communication Signals

Biomedicines ◽

10.3390/biomedicines9010079 ◽

2021 ◽

Vol 9 (1) ◽

pp. 79

Author(s):

Claudio Tabolacci ◽

Martina Cordella ◽

Sabrina Mariotti ◽

Stefania Rossi ◽

Cinzia Senatore ◽

...

Keyword(s):

Tumor Microenvironment ◽

Acquired Resistance ◽

Bioinformatic Analysis ◽

Interferon Γ ◽

Melanoma Cells ◽

Vascular Endothelial ◽

Therapeutic Success ◽

Communication Signals ◽

Proteasome Pathway ◽

Endothelial Growth Factor

The therapeutic success of BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) in BRAF-mutant melanoma is limited by the emergence of drug resistance, and several lines of evidence suggest that changes in the tumor microenvironment can play a pivotal role in acquired resistance. The present study focused on secretome profiling of melanoma cells sensitive or resistant to the BRAFi vemurafenib. Proteomic and cytokine/chemokine secretion analyses were performed in order to better understand the interplay between vemurafenib-resistant melanoma cells and the tumor microenvironment. We found that vemurafenib-resistant melanoma cells can influence dendritic cell (DC) maturation by modulating their activation and cytokine production. In particular, human DCs exposed to conditioned medium (CM) from vemurafenib-resistant melanoma cells produced higher levels of pro-inflammatory cytokines—that potentially facilitate melanoma growth—than DCs exposed to CM derived from parental drug-sensitive cells. Bioinformatic analysis performed on proteins identified by mass spectrometry in the culture medium from vemurafenib-sensitive and vemurafenib-resistant melanoma cells suggests a possible involvement of the proteasome pathway. Moreover, our data confirm that BRAFi-resistant cells display a more aggressive phenotype compared to parental ones, with a significantly increased production of interferon-γ, interleukin-8, vascular-endothelial growth factor, CD147/basigin, and metalloproteinase 2 (MMP-2). Plasma levels of CD147/basigin and MMP-2 were also measured before the start of therapy and at disease progression in a small group of melanoma patients treated with vemurafenib or vemurafenib plus cobimetinib. A significant increment in CD147/basigin and MMP-2 was observed in all patients at the time of treatment failure, strengthening the hypothesis that CD147/basigin might play a role in BRAFi resistance.

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Blocking Migration of Polymorphonuclear Myeloid-Derived Suppressor Cells Inhibits Mouse Melanoma Progression

Cancers ◽

10.3390/cancers13040726 ◽

2021 ◽

Vol 13 (4) ◽

pp. 726

Author(s):

Christopher Groth ◽

Ludovica Arpinati ◽

Merav E. Shaul ◽

Nina Winkler ◽

Klara Diester ◽

...

Keyword(s):

Tumor Progression ◽

Checkpoint Inhibitors ◽

Suppressor Cells ◽

Receptor Expression ◽

Myeloid Derived Suppressor Cells ◽

Melanoma Progression ◽

Relative Contribution ◽

Immunosuppressive Tumor Microenvironment ◽

Metastatic Sites

Background: Despite recent improvement in the treatment of malignant melanoma by immune-checkpoint inhibitors, the disease can progress due to an immunosuppressive tumor microenvironment (TME) mainly represented by myeloid-derived suppressor cells (MDSC). However, the relative contribution of the polymorphonuclear (PMN) and monocytic (M) MDSC subsets to melanoma progression is not clear. Here, we compared both subsets regarding their immunosuppressive capacity and recruitment mechanisms. Furthermore, we inhibited PMN-MDSC migration in vivo to determine its effect on tumor progression. Methods: Using the RET transgenic melanoma mouse model, we investigated the immunosuppressive function of MDSC subsets and chemokine receptor expression on these cells. The effect of CXCR2 inhibition on PMN-MDSC migration and tumor progression was studied in RET transgenic mice and in C57BL/6 mice after surgical resection of primary melanomas. Results: Immunosuppressive capacity of intratumoral M- and PMN-MDSC was comparable in melanoma bearing mice. Anti-CXCR2 therapy prolonged survival of these mice and decreased the occurrence of distant metastasis. Furthermore, this therapy reduced the infiltration of melanoma lesions and pre-metastatic sites with PMN-MDSC that was associated with the accumulation of natural killer (NK) cells. Conclusions: We provide evidence for the tumor−promoting properties of PMN-MDSC as well as for the anti-tumor effects upon their targeting in melanoma bearing mice.

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The effect of PEGylation on the efficacy and uptake of an immunostimulatory nanoparticle in the tumor immune microenvironment

Nanoscale Advances ◽

10.1039/d1na00308a ◽

2021 ◽

Author(s):

Wyatt M. Becicka ◽

Peter Bielecki ◽

Morgan Lorkowski ◽

Taylor J. Moon ◽

Yahan Zhang ◽

...

Keyword(s):

Tumor Microenvironment ◽

Immune Cells ◽

Innate Immune ◽

Innate Immune Cells ◽

Immune Microenvironment ◽

Tumor Immune Microenvironment ◽

Immunosuppressive Tumor Microenvironment

The efficacy of immunotherapies is often limited by the immunosuppressive tumor microenvironment, which is populated with dysfunctional innate immune cells. To reprogram the tumor-resident innate immune cells, we developed an...

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Immunomodulation by Inflammation during Liver and Gastrointestinal Tumorigenesis and Aging

International Journal of Molecular Sciences ◽

10.3390/ijms22052238 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2238

Author(s):

Nao Nagai ◽

Yotaro Kudo ◽

Daisuke Aki ◽

Hayato Nakagawa ◽

Koji Taniguchi

Keyword(s):

Colorectal Cancer ◽

Chronic Inflammation ◽

Antitumor Immunity ◽

Suppressor Cells ◽

Treg Cells ◽

Cytotoxic T Cell ◽

Myeloid Derived Suppressor Cells ◽

Pro Inflammatory Cytokines

Chronic inflammation is thought to promote tumorigenesis and metastasis by several mechanisms, such as affecting tumor cells directly, establishing a tumor-supporting microenvironment, enhancing tumor angiogenesis, and suppressing antitumor immunity. In this review, we discuss the recent advances in our understanding of how inflammation induces the immunosuppressive tumor microenvironment, such as increasing the level of pro-inflammatory cytokines, chemokines, and immunosuppressive molecules, inducing immune checkpoint molecules and cytotoxic T-cell exhaustion, and accumulating regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs). The suppression of antitumor immunity by inflammation is especially examined in the liver and colorectal cancer. In addition, chronic inflammation is induced during aging and causes age-related diseases, including cancer, by affecting immunity. Therefore, we also discuss the age-related diseases regulated by inflammation, especially in the liver and colon.

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