Deciphering and Reversing Tumor Immune Suppression

Motz, Greg; Coukos, George

doi:10.1016/j.immuni.2013.07.005

Cited by 510 publications

(436 citation statements)

References 174 publications

(214 reference statements)

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“…Moreover, TAM favor the local recruitment of Treg cells by secreting CCL22. 9 We have previously reported that the CD115 ligands M-CSF and IL-34, drive monocytes into IL-10 high IL-12 low immunoregulatory macrophages which are similar to ovarian cancer TAM. 5,10,11 They represent a robust model to decipher in vitro the biology of immunoregulatory macrophages.…”

Section: Introductionmentioning

confidence: 94%

The ecto-ATPDase CD39 is involved in the acquisition of the immunoregulatory phenotype by M-CSF-macrophages and ovarian cancer tumor-associated macrophages: Regulatory role of IL-27

et al. 2016

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(2016) The ectoATPDase CD39 is involved in the acquisition of the immunoregulatory phenotype by M-CSFmacrophages and ovarian cancer tumor-associated macrophages: Regulatory role of IL-27, OncoImmunology, 5:7, e1178025, DOI: 10.1080/2162402X.2016 Targeting mediators that control the generation or the differentiation of immunoregulatory macrophages represents a therapeutic challenge to overcome tumor-associated immunosuppression. The ectonucleotidase CD39 hydrolyzes ATP into extracellular adenosine that exhibits potent immunosuppressive properties when signaling through the A2A adenosine receptor. We report here that CD14 C CD163 C TAM isolated from ovarian cancer patients and macrophages generated in vitro with M-CSF, express high levels of the membrane ectonucleotidase CD39 compared to classically activated macrophages. The CD39 inhibitor POM-1 and adenosine deaminase (ADA) diminished some of the immunosuppressive functions of CD14 high CD163 high CD39 high macrophages, such as IL-10 secretion. We identified the cytokine IL-27, secreted by tumor-infiltrating neutrophils, located close to infiltrating CD163 C macrophages, as a major rheostat of CD39 expression and consequently, on the acquisition of immunoregulatory properties by macrophages. Accordingly, the depletion of IL-27 downregulated CD39 and PD-L1 expression as well as IL-10 secretion by M-CSF-macrophages. Collectively, these data suggest that CD39, drived by IL-27 and CD115 ligands in ovarian cancer, maintains the immunosuppressive phenotype of TAM. This work brings new information on the acquisition of immunosuppressive properties by tumor-infiltrating macrophages.

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Section: Introductionmentioning

confidence: 94%

The ecto-ATPDase CD39 is involved in the acquisition of the immunoregulatory phenotype by M-CSF-macrophages and ovarian cancer tumor-associated macrophages: Regulatory role of IL-27

et al. 2016

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“…Moreover, tumor-mediated suppression of immune responses, regulated by various immunosuppressive cell types such as myeloid-derived suppressor cells and regulatory T cells (T regs ) that reside in the tumor microenvironment, could potentially limit the therapeutic benefits of DC-based immunotherapy [22,23]. Therefore, the impact of cancer vaccines can only truly be evaluated when all these different players are taken into account.…”

Section: Therapeutic Vaccinations With Mrna-sonoporated Dcsmentioning

confidence: 99%

The potential of antigen and TriMix sonoporation using mRNA-loaded microbubbles for ultrasound-triggered cancer immunotherapy

Dewitte

Lint

Heirman

et al. 2014

Journal of Controlled Release

101

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Dendritic cell (DC)-based cancer vaccines, where the patient's own immune system is harnessed to target and destroy tumor tissue, has emerged as a potent therapeutic strategy. In the development of such DC vaccines, it is crucial to load the DCs with tumor antigens, and to simultaneously activate them to become more potent antigen-presenting cells. For this, we report on microbubbles, loaded with both antigen mRNA as well as immunomodulating TriMix mRNA, which can be used for the ultrasound-triggered transfection of DCs. In vivo experiments with in vitro sonoporated DCs, show the effective induction of antigen-specific T cells, resulting in specific lysis of antigen-expressing cells. Especially in a therapeutic setting, sonoporation with TriMix has a significant added value, resulting in a significant reduction of tumor outgrowth and a marked increase in overall survival. What is more, complete tumor regression was observed in 30% of the antigen+TriMix DC vaccinated animals, which also displayed long-term antigen-specific immunological memory. As a result, DC sonoporation using microbubbles loaded with a combination of antigen and TriMix mRNA can elicit powerful immune responses in vivo, and might serve as a potential tool for further in vivo DC vaccination applications.

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“…This in turn leads to hypoxia and lowering of the microenvironment pH, which further promotes tumor progression. At the same time hypo-perfusion and hypoxia compromise normal immune response, thus rendering the tumor impervious to the immune system [11,12] with an invasive and metastatic phenotype [13]. As expected, reduced blood supply also interferes with effective drug delivery to the tumor [9].…”

Section: Causes Of Insufficient Drug Delivery To Tumorsmentioning

confidence: 79%

Targeting Inflammation to Improve Tumor Drug Delivery

2017

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Inefficient delivery of drugs is a main cause of chemotherapy failure in hypo-perfused tumors. To enhance perfusion and drug delivery in these tumors, two strategies have been developed: vascular normalization, aiming at normalizing tumor vasculature and blood vessel leakiness; and stress alleviation, aiming at decompressing tumor vessels. Vascular normalization is based on antiangiogenic drugs, whereas stress alleviation on stroma-depleting agents. Here, an alternatively approach to normalize vessels is presented, considering that malignant tumors tend to develop at chronic inflammation sites. Similarly to tumor vessel leakiness, inflammation is also characterized by vascular hyper-permeability. Therefore, testing the ability of anti-inflammatory agents, such as non-steroidal anti-inflammatory drugs or inflammation resolution mediators, as an alternative way to increase tumor drug delivery, might prove promising.Keywords stress alleviation; vascular normalization; tumor perfusion; anti-inflammatory agents; inflammation resolution The Tumor microenvironment and drug deliveryTumors are complex tissues consisting of cancer cells and their microenvironment [1,2], which includes structural and cellular components. Structural components of the tumor microenvironment comprise tumor blood and lymphatic vessels, and the extracellular matrix (ECM) (see Glossary); while the stromal cell constituents [3] include angiogenic vascular cells (endothelial cells and pericytes), infiltrating immune cells, and cancer-associated fibroblasts (CAFs). Naturally, interactions between cancer cells and the various components of tumor microenvironment affect fundamental cancer cell properties such as proliferation, apoptosis, migration and invasion.It has been postulated that components and features of the tumor microenvironment may also set certain barriers with regard to the effective delivery of therapeutic agents, resulting in compromised therapeutic outcomes and decreased survival [4]. Chemotherapeutic drugs are, without a doubt, potent cytotoxic agents. However, they often fail to cure cancer due to the fact that they are unable to reach cancer cells within the tumor in sufficient amounts [5,6]. Hence, the discovery of more efficient approaches to enhance tumor drug delivery is imperative. Here, the main obstacles in drug delivery to the tumor are presented along with the approaches currently used to overcome them. Furthermore, the use of anti-inflammatory agents is proposed as a promising alternative approach to normalize vessels and improve therapy. Europe PMC Funders Group Causes of insufficient drug delivery to tumorsInefficient drug delivery may arise due to barriers posed by abnormal structure and function of tumor stroma, known as desmoplasia. Desmoplastic tumors are characterized by a dense ECM, containing increased levels of total fibrillar collagen, hyaluronan, fibronectin, proteoglycans and tenascin C [4], which also provides the tumor with a reservoir of growth factors eventually promoting its growth. The dense ...

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Deciphering and Reversing Tumor Immune Suppression

Cited by 510 publications

References 174 publications

The ecto-ATPDase CD39 is involved in the acquisition of the immunoregulatory phenotype by M-CSF-macrophages and ovarian cancer tumor-associated macrophages: Regulatory role of IL-27

The ecto-ATPDase CD39 is involved in the acquisition of the immunoregulatory phenotype by M-CSF-macrophages and ovarian cancer tumor-associated macrophages: Regulatory role of IL-27

The potential of antigen and TriMix sonoporation using mRNA-loaded microbubbles for ultrasound-triggered cancer immunotherapy

Targeting Inflammation to Improve Tumor Drug Delivery

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