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

Cancers ◽  
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.

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

Biomolecules ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 1087 ◽  
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.

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

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...

scholarly journals Therapeutic Implications of Tumor Microenvironment in Lung Cancer: Focus on Immune Checkpoint Blockade

2022 ◽  
Vol 12 ◽  
Author(s):  
Carlo Genova ◽  
Chiara Dellepiane ◽  
Paolo Carrega ◽  
Sara Sommariva ◽  
Guido Ferlazzo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Suppressor Cells ◽  
Regulatory Elements ◽  
Immune Checkpoint Blockade ◽  
Therapeutic Implications ◽  
Investigational Agents

In the last decade, the treatment of non-small cell lung cancer (NSCLC) has been revolutionized by the introduction of immune checkpoint inhibitors (ICI) directed against programmed death protein 1 (PD-1) and its ligand (PD-L1), or cytotoxic T lymphocyte antigen 4 (CTLA-4). In spite of these improvements, some patients do not achieve any benefit from ICI, and inevitably develop resistance to therapy over time. Tumor microenvironment (TME) might influence response to immunotherapy due to its prominent role in the multiple interactions between neoplastic cells and the immune system. Studies investigating lung cancer from the perspective of TME pointed out a complex scenario where tumor angiogenesis, soluble factors, immune suppressive/regulatory elements and cells composing TME itself participate to tumor growth. In this review, we point out the current state of knowledge involving the relationship between tumor cells and the components of TME in NSCLC as well as their interactions with immunotherapy providing an update on novel predictors of benefit from currently employed ICI or new therapeutic targets of investigational agents. In first place, increasing evidence suggests that TME might represent a promising biomarker of sensitivity to ICI, based on the presence of immune-modulating cells, such as Treg, myeloid derived suppressor cells, and tumor associated macrophages, which are known to induce an immunosuppressive environment, poorly responsive to ICI. Consequently, multiple clinical studies have been designed to influence TME towards a pro-immunogenic state and subsequently improve the activity of ICI. Currently, the mostly employed approach relies on the association of “classic” ICI targeting PD-1/PD-L1 and novel agents directed on molecules, such as LAG-3 and TIM-3. To date, some trials have already shown promising results, while a multitude of prospective studies are ongoing, and their results might significantly influence the future approach to cancer immunotherapy.

scholarly journals MDMX phosphorylation-dependent p53 downregulation contributes to an immunosuppressive tumor microenvironment

2020 ◽  
Vol 12 (9) ◽  
pp. 713-722
Author(s):  
Bing Wang ◽  
Chuan-Bian Lim ◽  
Jiawei Yan ◽  
Lizhen Li ◽  
Jufang Wang ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cell ◽  
Growth Delay ◽  
Dependent Manner ◽  
Tumor Growth Delay ◽  
M1 Polarization ◽  
Tumor Immune Microenvironment ◽  
Immunosuppressive Tumor Microenvironment ◽  
Potential Strategy

Abstract A role of tumor-suppressive activity of p53 in the tumor microenvironment (TME) has been implicated but remains fairly understudied. To address this knowledge gap, we leveraged our MdmxS314A mice as recipients to investigate how implanted tumor cells incapacitate host p53 creating a conducive TME for tumor progression. We found that tumor cell-associated stress induced p53 downregulation in peritumor cells via an MDMX-Ser314 phosphorylation-dependent manner. As a result, an immunosuppressive TME was developed, as reflected by diminished immune cell infiltration into tumors and compromised macrophage M1 polarization. Remarkably, ablation of MDMX-Ser314 phosphorylation attenuated p53 decline in peritumor cells, which was associated with mitigation of immunosuppression and significant tumor growth delay. Our data collectively uncover a novel role of p53 in regulating the tumor immune microenvironment, suggesting that p53 restoration in the TME can be exploited as a potential strategy of anticancer therapy.

Potential alteration of tumor microenvironments by β-mercaptoethanol

2020 ◽  
Author(s):  
Robert E Click
Keyword(s):  
Molecular Weight ◽  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Tumor Antigens ◽  
Checkpoint Inhibitors ◽  
Survival Rates ◽  
Suppressor Cells ◽  
Low Molecular Weight ◽  
Uptake Inhibition ◽  
Tumor Microenvironments

The therapeutic effectiveness of immune checkpoint inhibitors in cancer patients is quite profound. However, it is generally accepted that further progress is curtailed by accompanying adverse events and by low cure rates linked to the tumor microenvironment. The multitudes of immune processes altered by low-molecular-weight thiols published over the past decades suggest they have potential to alter tumor microenvironment processes which could result in an increase in immune checkpoint inhibitor survival rates. Based on one of the most studied and most potent low-molecular-weight thiols, β-mercaptoethanol (BME), it is proposed that clinical assessment be undertaken to identify any BME benefits with relevance for proliferation/differentiation of immune cells, lymphocyte exhaustion, immunogenicity of tumor antigens and inactivation of suppressor cells/factors. The BME alterations projected to be most effective are: maintenance/replacement of glutathione in lymphocytes via facilitation of cysteine uptake, inhibition of suppressor cells/soluble factors and inactivation of free-radical, reactive oxygen species.

EXTRATUMOR MICROENVIRONMENT IN RENAL CELL CARCINOMA

2021 ◽  
Vol 2 (4) ◽  
pp. 5-12
Author(s):  
Mirzagaleb Tillyashaykhov ◽  
◽  
Elena Boyko ◽  
Shakhnoza Jumaniyazova
Keyword(s):  
Renal Cell Carcinoma ◽  
Tumor Microenvironment ◽  
Cell Carcinoma ◽  
Immune Checkpoint ◽  
Renal Cell ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Immune Surveillance ◽  
Suppressor Cells ◽  
Animal Tumor

The review is focused on studying the immunosuppressive mechanisms acting in the microenvironment of renal cell carcinoma tumors. The report contains a collection of basic literature materials on the study of tumor growth factors that boost tumor cell proliferation and metastasis. The tumor microenvironment (TME) limits the immune surveillance of tumor-associated antigens and the effectiveness of immune checkpoint inhibitors. Although renal cell carcinoma is one of several tumor types sensitive to immune checkpoint inhibitors, the efficacy of these agents is likely to be limited by different tumor-infiltrating myeloid cells of bone marrow that make up the TME. Several strategies aimed at eliminating the onset of these cells in tumor tissue or neutralizing their immunosuppressive function have shown encouraging results in animal tumor models and clinical trials.Keywords: cytotoxic T lymphocytes (CTL), immune checkpoint inhibitor (ICI), tumor microenvironment (MEV), myeloid-derived suppressor cells (MDSC), regulatory T cells (Tregs), renal cell carcinoma (RCC), tumor-associated macrophages (TAM), vascular endothelial growth factor (VEGF)

scholarly journals Myeloid Cells in the Tumor Microenvironment: Modulation of Tumor Angiogenesis and Tumor Inflammation

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Michael C. Schmid ◽  
Judith A. Varner
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Angiogenesis ◽  
Malignant Tumors ◽  
Critical Role ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Myeloid Cell ◽  
Promote Tumor Growth ◽  
Bone Marrow Derived Cells

Myeloid cells are a heterogeneous population of bone marrow-derived cells that play a critical role during growth and metastasis of malignant tumors. Tumors exhibit significant myeloid cell infiltrates, which are actively recruited to the tumor microenvironment. Myeloid cells promote tumor growth by stimulating tumor angiogenesis, suppressing tumor immunity, and promoting metastasis to distinct sites. In this review, we discuss the role of myeloid cells in promoting tumor angiogenesis. Furthermore, we describe a subset of myeloid cells with immunosuppressive activity (known as myeloid-derived suppressor cells). Finally, we will comment on the mechanisms regulating myeloid cell recruitment to the tumor microenvironment and on the potential of myeloid cells as new targets for cancer therapy.

scholarly journals Overcoming the Immunosuppressive Tumor Microenvironment in Multiple Myeloma

Cancers ◽  
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.

scholarly journals Oncolytic virotherapy reverses the immunosuppressive tumor microenvironment and its potential in combination with immunotherapy

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yalei Zhang ◽  
Ye Li ◽  
Kun Chen ◽  
Ling Qian ◽  
Peng Wang
Keyword(s):  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Oncolytic Viruses ◽  
Tumor Resistance ◽  
Systemic Delivery ◽  
Future Directions ◽  
Immunosuppressive Tumor Microenvironment ◽  
Proinflammatory Factors

AbstractIt has been intensively reported that the immunosuppressive tumor microenvironment (TME) results in tumor resistance to immunotherapy, especially immune checkpoint blockade and chimeric T cell antigen therapy. As an emerging therapeutic agent, oncolytic viruses (OVs) can specifically kill malignant cells and modify immune and non-immune TME components through their intrinsic properties or genetically incorporated with TME regulators. Strategies of manipulating OVs against the immunosuppressive TME include serving as a cancer vaccine, expressing proinflammatory factors and immune checkpoint inhibitors, and regulating nonimmune stromal constituents. In this review, we summarized the mechanisms and applications of OVs against the immunosuppressive TME, and strategies of OVs in combination with immunotherapy. We also introduced future directions to achieve efficient clinical translation including optimization of preclinical models that simulate the human TME and achieving systemic delivery of OVs.

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

2021 ◽  
Vol 9 (12) ◽  
pp. 2569
Author(s):  
Manasi Sawant ◽  
Sadia Benamrouz-Vanneste ◽  
Anthony Mouray ◽  
Peggy Bouquet ◽  
Nausicaa Gantois ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cryptosporidium Parvum ◽  
Gastrointestinal Disease ◽  
Suppressor Cells ◽  
Interferon Γ ◽  
Digestive Cancer ◽  
Immune Suppressor Cells ◽  
Extracellular Matrix Components ◽  
Immunosuppressive Tumor Microenvironment ◽  
Life Threatening

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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