Targeting MDSC for Immune-Checkpoint Blockade in Cancer Immunotherapy: Current Progress and New Prospects

Li, Tianhang; Liu, Tianyao; Zhu, Wenjie; Xie, Shangxun; Zhao, Zihan; Feng, Baofu; Guo, Hongqian; Yang, Rong

doi:10.1177/11795549211035540

Cited by 50 publications

(24 citation statements)

References 189 publications

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“…Many strategies have been tested to block the immune suppression activity of MDSCs for cancer treatment [32][33][34], among which depletion of MDSCs by anti-Gr-1 antibodies or cytotoxic chemotherapy drugs(such as gemcitabine and 5-uorouracil) were proved effective to enhance T cell antitumor response and inhibit tumor growth in preclinical tumor models [35][36][37][38]. However, anti-Gr-1 antibodies may also deplete neutrophils since Gr-1 is a general marker for granulocyte, more importantly, Gr-1 antigen is not expressed on human MDSCs.…”

Section: Discussionmentioning

confidence: 99%

Targeting Depletion of Myeloid-Derived Suppressor Cells Enhances PD-L1 Blockade Efficacy in Gastric Cancer

Tang

Zhou

et al. 2022

Preprint

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Background Gastric cancer (GC) remains one of the most common malignancieswith poor prognosis worldwide. Immunotherapy based on PD-1/PD-L1 immune checkpoints has achieved robust and durable responses in various types of cancer, but only a subset of gastric cancer patients benefits from it.Myeloid-derived suppressor cells (MDSCs) have been demonstrated to suppress antitumor immunityand induceresistanceto PD-1/PD-L1 blockade immunotherapy. Death receptor5 (DR5), a receptor of TNF-related apoptosis-inducing ligand(TRAIL), is upregulated in MDSCs and is also commonly expressed on cancer cells, making it a desirable target for both MDSCs and DR5-positive GC. In this study, we evaluated the MDSCs depleting and immune modulating effect of the agonist DR5 antibody (MD5-1), and tested the therapeutic effectof targeting DR5 in combination with anti-PD-L1 as a new strategyfor the treatment of GC. Methods The MDSCs and their DR5 expression insyngeneic GC murine model were evaluated. TheMDSCs depleting effect by MD5-1 wereinvestigated. We compared the antitumor efficacy of MD5-1 in GC bearing T cell-deficient nude mice andsyngeneic 615 mice, and assessed its immune correlates. The antitumor effect of MD5-1 combininganti-PD-L1 in syngeneic GC murine model were tested, the tumor growth, mice survival and intratumoral T cell infiltration and activation were evaluated. Results The MDSCs accumulate in the gastric tumor-bearing 615 mice express high levels of DR5. Targeting DR5 using MD5-1specifically depleted MDSCs and enhancedT cell antitumor response, resulted in tumor growth inhibition.MD5-1 enhanced the antitumor effect of anti-PD-L1 antibody, led to complete regression in 40% ofestablished tumors and significantly extended the survival tumor-bearing mice. The enhanced antitumor effect by MD5-1 combining anti-PD-L1 was associatedwith increased CD8+ T cell infiltration and activation. Conclusions These results show that targeting DR5 enhances the antitumor effect of PD-L1 blockadetherapy in gastric cancer through eliminating MDSCs and improving CD8+T cell antitumor response.Thus, targeting DR5 in combination with anti-PD-L1 may be a novel immunotherapy strategy forgastric cancer.

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Section: Discussionmentioning

confidence: 99%

Targeting Depletion of Myeloid-Derived Suppressor Cells Enhances PD-L1 Blockade Efficacy in Gastric Cancer

Tang

Zhou

et al. 2022

Preprint

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“…Several molecules can be targeted to improve immune checkpoint inhibition by regulating MDSCs. A previous study with murine rhabdomyosarcoma showed that CXCR2-positive MDSCs inhibited the antitumor effect of anti-PD-1 antibody treatment and that anti-CXCR2 monoclonal antibody therapy enhanced it ( 30 , 31 ). It has been reported that Sema4D induced MDSC in the tumor microenvironment ( 32 ) and that head and neck squamous cell carcinoma patients with high plasma Sema4D levels had less infiltration of immune cells into the tumor microenvironment ( 33 ).…”

Section: Discussionmentioning

confidence: 99%

Principal component analysis of early immune cell dynamics during pembrolizumab treatment of advanced urothelial carcinoma

et al. 2022

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Immune checkpoint inhibitors have been approved as second-line therapy for patients with advanced urothelial carcinoma (UC). However, which patients will obtain clinical benefit remains to be determined. To identify predictive biomarkers for the pembrolizumab (PEM) response early during treatment, the present study investigated 31 patients with chemotherapy-resistant recurrent or metastatic UC who received 200 mg PEM intravenously every 3 weeks. Blood was taken just before the first dose and again before the second dose, and the peripheral blood mononuclear cells of all 31 pairs of blood samples were immune phenotyped by flow cytometry. Data were assessed by principal component analysis (PCA), correlation analysis and Cox proportional hazards modeling in order to comprehensively determine the effects of PEM on peripheral mononuclear immune cells. Absolute counts of CD45RA+CD27-CCR7- terminally differentiated CD8+ T cells and KLRG1+CD57+ senescent CD8+ T cells were significantly increased after PEM administration (P=0.042 and P=0.043, respectively). Senescent and exhausted CD4 + and CD8 + T cell dynamics were strongly associated with each other. By contrast, counts of monocytic myeloid-derived suppressor cells (mMDSCs) were not associated with other immune cell phenotypes. The results of PCA and non-hierarchical clustering of patients suggested that excessive T cell senescence and differentiation early during treatment were not necessarily associated with a survival benefit. However, decreased mMDSC counts after PEM were associated with improved overall survival. In conclusion, early on-treatment peripheral T cell status was associated with response to PEM; however, it was not associated with clinical benefit. By contrast, decreased peripheral mMDSC counts did predict improved overall survival.

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“…It has been reported that MDSCs are profoundly immune-suppressive cells in the TME that can promote tumor growth, angiogenesis, metastasis, and contribute to resistance to immunotherapy through inhibition of T-cell and NK-cell activity, as well as activation of M2 macrophage and Treg. 167 Therefore, elimination of MDSCs or inhibition of their activities can improve the suppression of the TME and enhance cancer immunotherapeutic efficacy. So far, many nanoparticles have been designed to target MDSCs to deplete these cells or inhibit their functions for improving cancer immunotherapy (Table 2).…”

Section: Nanoparticles For Modulating Mdscsmentioning

confidence: 99%

Targeting the innate immune system with nanoparticles for cancer immunotherapy

Zhang

et al. 2022

J. Mater. Chem. B

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Targeting MDSC for Immune-Checkpoint Blockade in Cancer Immunotherapy: Current Progress and New Prospects

Cited by 50 publications

References 189 publications

Targeting Depletion of Myeloid-Derived Suppressor Cells Enhances PD-L1 Blockade Efficacy in Gastric Cancer

Targeting Depletion of Myeloid-Derived Suppressor Cells Enhances PD-L1 Blockade Efficacy in Gastric Cancer

Principal component analysis of early immune cell dynamics during pembrolizumab treatment of advanced urothelial carcinoma

Targeting the innate immune system with nanoparticles for cancer immunotherapy

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