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Targeting MDSC in Cancer Therapy
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Targeting MDSC in Cancer Therapy

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 16655

Special Issue Editor

Prof. Dr. Sherven Sharma

E-Mail Website
Guest Editor
Department of Medicine, UCLA Lung Cancer Research Program, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
Interests: therapeutic cancer vaccines; tumor immunology; immune suppression
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer program cellular infiltrates sustain a dysregulated inflammation that is hypo-responsive to the cancer. Contributing to the cellular inflammatory infiltrates are myeloid-derived suppressor cells (MDSC) that negatively modulate immune responses and promote tumor angiogenesis, drug resistance, tumor progression, and metastases. MDSCs are a heterogeneous population of immature myeloid cells consisting of myeloid progenitors and precursors of macrophages, granulocytes, and dendritic cells (DC). Increases in the number of MDSCs evoke strong natural suppressive activity in cancer. MDSCs suppress T cell and NK cell activity. Progressive tumor growth is associated with the down-regulation of T cell responses, and MDSCs are involved in negative immunoregulatory mechanisms. Although cancer immunotherapy offers an attractive therapeutic option, activation of the immune system alone is not sufficient for antitumor activity. Targeting pathways of immune activation and mechanisms of immune suppression presents an attractive therapeutic opportunity to combat cancer. Targeting MDSCs may improve cancer immunotherapy.

Prof. Dr. Sherven Sharma
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Cancer
  • Myeloid-derived suppressor cells (MDSC)
  • Immune activation
  • Immune suppression
  • Tumor microenvironment (TME)
  • Metastasis
  • Angiogenesis
  • Drug resistance

Published Papers (3 papers)

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Research

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16 pages, 3650 KiB  
Article
Differential Targeting of Gr-MDSCs, T Cells and Prostate Cancer Cells by Dactolisib and Dasatinib
by Guoqiang Liu, Zhijian Jin and Xin Lu
Int. J. Mol. Sci. 2020, 21(7), 2337; https://doi.org/10.3390/ijms21072337 - 27 Mar 2020
Cited by 10 | Viewed by 4015
Abstract
Granulocytic myeloid-derived suppressor cells (Gr-MDSCs) promote immune evasion and resistance to immunotherapeutics in a variety of malignancies. Our previous study showed that dual PI3K/mTOR inhibitor Dactolisib impaired the viability and immunosuppressive function of Gr-MDSCs, and significantly synergized with immune checkpoint blockade (ICB) antibodies [...] Read more.
Granulocytic myeloid-derived suppressor cells (Gr-MDSCs) promote immune evasion and resistance to immunotherapeutics in a variety of malignancies. Our previous study showed that dual PI3K/mTOR inhibitor Dactolisib impaired the viability and immunosuppressive function of Gr-MDSCs, and significantly synergized with immune checkpoint blockade (ICB) antibodies targeting PD1 and CTLA4 to eradicate metastatic castration-resistant prostate cancer (CRPC) in a preclinical transgenic mouse model. On the contrary, tyrosine kinase inhibitor Dasatinib diminished tumor-infiltrating T lymphocytes and showed no synergic activity with ICB. The understanding of the distinct effects of Dactolisib and Dasatinib on Gr-MDSCs, T cells and prostate neoplastic cells is inadequate, limiting the clinical translation of the combination immunotherapy. To address this question, we applied Reverse Phase Protein Array (RPPA) to profile 297 proteins and protein phosphorylation sites of Gr-MDSCs, T cells and prostate cancer cells isolated from the CRPC model. We found cell type-specific protein expression patterns and highly selective targets by the two drugs, including preferential inhibition of phospho-4E-BP1 in Gr-MDSCs by Dactolisib and preferential suppression of phospho-Src and phospho-p38 MAPK in T cells. Furthermore, transcriptomic profiling of Gr-MDSCs treated with the two inhibitors revealed downregulation of mitochondrial respiration pathways by Dactolisib but not Dasatinib. Overall, these results provide important mechanistic insight into the efficacious combination of Dactolisib and ICB as well as the detrimental effect of Dasatinib on anti-tumor immunity. Full article
(This article belongs to the Special Issue Targeting MDSC in Cancer Therapy)
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Review

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13 pages, 2236 KiB  
Review
Understanding the Differentiation, Expansion, Recruitment and Suppressive Activities of Myeloid-Derived Suppressor Cells in Cancers
by Hui Xuan Lim, Tae Sung Kim and Chit Laa Poh
Int. J. Mol. Sci. 2020, 21(10), 3599; https://doi.org/10.3390/ijms21103599 - 20 May 2020
Cited by 35 | Viewed by 6016
Abstract
There has been a great interest in myeloid-derived suppressor cells (MDSCs) due to their biological functions in tumor-mediated immune escape by suppressing antitumor immune responses. These cells arise from altered myelopoiesis in response to the tumor-derived factors. The most recognized function of MDSCs [...] Read more.
There has been a great interest in myeloid-derived suppressor cells (MDSCs) due to their biological functions in tumor-mediated immune escape by suppressing antitumor immune responses. These cells arise from altered myelopoiesis in response to the tumor-derived factors. The most recognized function of MDSCs is suppressing anti-tumor immune responses by impairing T cell functions, and these cells are the most important players in cancer dissemination and metastasis. Therefore, understanding the factors and the mechanism of MDSC differentiation, expansion, and recruitment into the tumor microenvironment can lead to its control. However, most of the studies only defined MDSCs with no further characterization of granulocytic and monocytic subsets. In this review, we discuss the mechanisms by which specific MDSC subsets contribute to cancers. A better understanding of MDSC subset development and the specific molecular mechanism is needed to identify treatment targets. The understanding of the specific molecular mechanisms responsible for MDSC accumulation would enable more precise therapeutic targeting of these cells. Full article
(This article belongs to the Special Issue Targeting MDSC in Cancer Therapy)
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23 pages, 4061 KiB  
Review
Lung Macrophage Functional Properties in Chronic Obstructive Pulmonary Disease
by Kentaro Akata and Stephan F. van Eeden
Int. J. Mol. Sci. 2020, 21(3), 853; https://doi.org/10.3390/ijms21030853 - 28 Jan 2020
Cited by 43 | Viewed by 6250
Abstract
Chronic obstructive pulmonary disease (COPD) is caused by the chronic exposure of the lungs to toxic particles and gases. These exposures initiate a persistent innate and adaptive immune inflammatory response in the airways and lung tissues. Lung macrophages (LMs) are key innate immune [...] Read more.
Chronic obstructive pulmonary disease (COPD) is caused by the chronic exposure of the lungs to toxic particles and gases. These exposures initiate a persistent innate and adaptive immune inflammatory response in the airways and lung tissues. Lung macrophages (LMs) are key innate immune effector cells that identify, engulf, and destroy pathogens and process inhaled particles, including cigarette smoke and particulate matter (PM), the main environmental triggers for COPD. The number of LMs in lung tissues and airspaces is increased in COPD, suggesting a potential key role for LMs in initiating and perpetuating the chronic inflammatory response that underpins the progressive nature of COPD. The purpose of this brief review is to discuss the origins of LMs, their functional properties (chemotaxis, recruitment, mediator production, phagocytosis and apoptosis) and changes in these properties due to exposure to cigarette smoke, ambient particulate and pathogens, as well as their persistent altered functional properties in subjects with established COPD. We also explore the potential to therapeutically modulate and restore LMs functional properties, to improve impaired immune system, prevent the progression of lung tissue destruction, and improve both morbidity and mortality related to COPD. Full article
(This article belongs to the Special Issue Targeting MDSC in Cancer Therapy)
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