Characterization of the nature of granulocytic myeloid-derived suppressor cells in tumor-bearing mice

Colorectal cancer (CRC) remains a devastating human malignancy with poor prognosis. Of the various factors, immune evasion mechanisms play pivotal roles in CRC progression and impede the effects of cancer therapy. Myeloid-derived suppressor cells (MDSCs) constitute an immature population of myeloid cells that are typical during tumor progression. These cells have the ability to induce strong immunosuppressive effects within the tumor microenvironment (TME) and promote CRC development. Indeed, MDSCs have been shown to accumulate in both tumor-bearing mice and CRC patients, and may therefore become an obstacle for cancer immunotherapy. Consequently, numerous studies have focused on the characterization of MDSCs and their immunosuppressive capacity, as well as developing novel approaches to suppress MDSCs function with different approaches. Current therapeutic strategies that target MDSCs in CRC include inhibition of their recruitment and alteration of their function, alone or in combination with other therapies including chemotherapy, radiotherapy and immunotherapy. Herein, we summarize the recent roles and mechanisms of MDSCs in CRC progression. In addition, a brief review of MDSC-targeting approaches for potential CRC therapy is presented.

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IL‐33 inhibits the differentiation and immunosuppressive activity of granulocytic myeloid‐derived suppressor cells in tumor‐bearing mice

Immunology and Cell Biology ◽

10.1038/icb.2016.72 ◽

2016 ◽

Vol 95 (1) ◽

pp. 99-107 ◽

Cited By ~ 12

Author(s):

Hui Xuan Lim ◽

Seulah Choi ◽

Daeho Cho ◽

Tae Sung Kim

Keyword(s):

Suppressor Cells ◽

Myeloid Derived Suppressor Cells ◽

Immunosuppressive Activity ◽

Tumor Bearing

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Long noncoding RNA Pvt1 regulates the immunosuppression activity of granulocytic myeloid-derived suppressor cells in tumor-bearing mice

Molecular Cancer ◽

10.1186/s12943-019-0978-2 ◽

2019 ◽

Vol 18 (1) ◽

Cited By ~ 40

Author(s):

Yu Zheng ◽

Xinyu Tian ◽

Tingting Wang ◽

Xueli Xia ◽

Fenghua Cao ◽

...

Keyword(s):

Long Noncoding Rna ◽

Noncoding Rna ◽

Suppressor Cells ◽

Myeloid Derived Suppressor Cells ◽

Tumor Bearing

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Metformin inhibits the function of granulocytic myeloid-derived suppressor cells in tumor-bearing mice

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2019.109458 ◽

2019 ◽

Vol 120 ◽

pp. 109458 ◽

Cited By ~ 5

Author(s):

Peiqi Xu ◽

Kai Yin ◽

Xinyi Tang ◽

Jie Tian ◽

Yue Zhang ◽

...

Keyword(s):

Suppressor Cells ◽

Myeloid Derived Suppressor Cells ◽

Tumor Bearing

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ATIM-40. CIRCULATING MYELOID-DERIVED SUPPRESSOR CELLS PREDICT FAVORABLE RESPONSE TO IMMUNE CHECKPOINT THERAPY IN A RANDOMIZED TRIAL OF NIVOLUMAB AND BEVACIZUMAB IN RECURRENT GBM

Neuro-Oncology ◽

10.1093/neuonc/noz175.039 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi10-vi10

Author(s):

Manmeet Ahluwalia ◽

Matthew Grabowski ◽

Tyler Alban ◽

Balint Otvos ◽

Defne Bayik ◽

...

Keyword(s):

T Cells ◽

Immune Cell ◽

Suppressor Cells ◽

Post Treatment ◽

Myeloid Derived Suppressor Cells ◽

Phase 2 Study ◽

First Recurrence ◽

Insight Into

Abstract Glioblastoma (GBM) creates an immunosuppressive environment that presents a challenge to efficacy of immunotherapeutic approaches. Results from the CheckMate-143 trial demonstrated responses in 8% of patients with nivolumab, underscoring the need for further insight into the mechanisms and markers of immune suppression and response. Given a limited set of biomarkers predictive of immunotherapy response in GBM, we explored the changes in immune cell populations in nivolumab and bevacizumab-treated GBM patients pre and post-treatment in order to help predict response. In these studies, we utilized traditional and newly developed approaches, including mass cytometry time-of-flight (CyTOF), single-cell RNA sequencing, and 10X Genomics simultaneous cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq). We analyzed patients’ samples in a randomized, phase 2 study of nivolumab and bevacizumab at GBM first recurrence (NCT03452579). Nine patients were identified as responders or non-responders at 8 weeks after therapy initiation. Utilizing peripheral blood samples, we observed a 6.4-fold decrease in immunosuppressive myeloid-derived suppressor cells (MDSCs) between baseline and first imaging follow-up in responders compared to non-responders, with a 4.9-fold decrease in the granulocytic MDSC (G-MDSC) subtype in responders over non-responders. While no significant changes in overall T-cell numbers were noted, expression of PD-1 on CD4+ T cells was significantly elevated at baseline and follow-up in responders as compared to non-responders – signatures which were confirmed by CyTOF. Given these immunophenotypic changes, preliminary results of a detailed investigation of this cohort by CITE-seq indicate that responders had increased IL7R-positive T cells post-treatment, which was not observed in non-responders. These results are currently being validated in an additional 40 patients that have been enrolled. Altogether, differences in immunophenotypes that were specific to responders and non-responders were observed, and characterization of these immune populations may be helpful in identifying GBM patients likely to benefit from immunotherapy.

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Anti-Gr-1 antibody depletion fails to eliminate hepatic myeloid-derived suppressor cells in tumor-bearing mice

Journal of Leukocyte Biology ◽

10.1189/jlb.0212059 ◽

2012 ◽

Vol 92 (6) ◽

pp. 1199-1206 ◽

Cited By ~ 42

Author(s):

Chi Ma ◽

Tamar Kapanadze ◽

Jaba Gamrekelashvili ◽

Michael P. Manns ◽

Firouzeh Korangy ◽

...

Keyword(s):

Suppressor Cells ◽

Myeloid Derived Suppressor Cells ◽

Tumor Bearing

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Independent mechanisms of T cell-suppression by subpopulations of myeloid-derived suppressor cells (MDSC) in tumor-bearing hosts

Journal for ImmunoTherapy of Cancer ◽

10.1186/2051-1426-1-s1-p193 ◽

2013 ◽

Vol 1 (Suppl 1) ◽

pp. P193

Author(s):

Patrick L Raber ◽

Paul Thevenot ◽

Rosa Sierra ◽

Dorota Wyczechowska ◽

Maria E Ramirez ◽

...

Keyword(s):

T Cell ◽

Suppressor Cells ◽

Myeloid Derived Suppressor Cells ◽

Tumor Bearing ◽

T Cell Suppression ◽

Cell Suppression

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Development of myeloid-derived suppressor cells (MDSC) targeted therapy for the treatment of cisplatin-resistant bladder cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.415 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 415-415

Author(s):

Yuji Takeyama ◽

Minoru Kato ◽

Yasuomi Shimizu ◽

Kosuke Hamada ◽

Taro Iguchi ◽

...

Keyword(s):

Gene Expression ◽

Bladder Cancer ◽

Cell Lines ◽

Cancer Cell ◽

Suppressor Cells ◽

Bladder Cancer Cell ◽

Myeloid Derived Suppressor Cells ◽

Expression Levels ◽

Tumor Bearing ◽

Gene Expression Levels

415 Background: The emergence of immune checkpoint inhibitors (ICI) has brought hope for cure and survival for those suffering from various cancers, including bladder cancer. However, the response rate of ICI monotherapy is modest, and recent reports indicate that myeloid-derived suppressor cells (MDSC) might play a role in the resistant mechanism of ICI. In this study, we assess the effect of chemokine signal on the proliferation of bladder cancer and investigate whether MDSC could be a new target for the treatment of cisplatin-resistant bladder cancer. Methods: We established a cisplatin resistant strain (MB49R) of mice bladder cancer cell line MB49, and examined the alteration of the expression levels of inflammatory chemokines by chemokine array. Next, we isolated MDSCs from spleen and tumor in tumor-bearing mice to examine gene expression levels of chemokine receptors (CXCR2 and CCR2) and immunosuppression genes (Arg-1 and iNOS). Furthermore, we assessed the efficacy of CDDP, α-PD-L1 and chemokine antagonists against the proliferation of tumors in MB49 and MB49R xenograft models. Results: Expression levels of CCL2 and CXCL1/2, which are involved in the migration of MDSC, were significantly increased in the culture supernatant of MB49R compared to those in MB49 cell lines. This result was confirmed by real-time RT-qPCR of tumor extract, and this increase was also observed in human bladder cancer cell lines (T24 and T24R). CXCR2 and CCR2 were highly expressed in PMN-MDSC and M-MDSC, respectively, which were isolated from spleen or tumors in tumor-bearing mice, and gene expression levels of Arg-1 and iNOS were dramatically increased in M-MDSCs from the tumor tissues compared to those from spleen. Also, analysis by flow cytometry revealed that PMN-MDSC dramatically decreased in MB49R compared to parental MB49 tumors, while the proportion of M-MDSC was not changed in MB49R, which indicates that M-MDSC could be a target for the treatment of CDDP resistant bladder cancer. Conclusions: The results in the present study might indicate that the combination treatment with ICI and MDSC-targeting therapy could be an option for the treatment of cisplatin-resistant bladder cancer.

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