Myeloid-derived Suppressor Cells In Tumor Microenvironment Research Articles

STAT3 promotes differentiation of monocytes to MDSCs via CD39/CD73-adenosine signal pathway in oral squamous cell carcinoma.

Myeloid-derived suppressor cells (MDSCs) are one of the tumor-infiltrating immune cell population, which play a powerful role in inhibiting anti-tumor immune response. Our previous studies have shown that STAT3 blockade can decrease the number of MDSCs in tumor microenvironment. However, it is unclear for the molecular mechanism of down-regulation MDSCs with STAT3 inhibitor. In this study, we first detected and analyzed the expression of p-STAT3, CD33, CD14, CD39 and CD73 via oral squamous cell carcinoma (OSCC) tissue array. We found that p-STAT3 was positively correlated with CD14, CD33, CD39, and CD73 in OSCC patient specimens. Then we found STAT3 blockade with S3I-201 reduced the expression of CD39/CD73 and the synthesis of adenosine, as well as inhibiting monocytes to MDSCs differentiation in vitro. Furthermore, we found that S3I-201 displayed prominent anti-tumor efficacy in C3H/He OSCC mouse model via inhibiting CD39/CD73-adenosine signal pathway and decreasing MDSCs. These results suggest that STAT3 signal can induce the differentiation of monocytes into MDSCs in tumor microenvironment depending on CD39/CD73-adenosine signal pathway and STAT3 blockade is a promising therapeutic strategy for OSCC.

SPLUNC1 regulates LPS-induced progression of nasopharyngeal carcinoma and proliferation of myeloid-derived suppressor cells.

Nasopharyngeal carcinoma (NPC) is one of the aggressive malignant tumors with high mortality, and the proliferation of myeloid-derived suppressor cells (MDSCs) could promote the metastasis of NPC through inhibiting the function of T cells. Meanwhile, SPLUNC1 was known to inhibit the malignant behavior of NPC cells, while the detailed function of SPLUNC1 in LPS-modified immune microenvironment of NPC remains unclear. To assess the impact of SPLUNC1 in immune microenvironment during the progression of NPC, NPC cells were exposed to LPS and then co-cultured with MDSCs for 48h. RT-qPCR and western blot were performed to evaluate the mRNA and protein level of SPLUNC1, CXCL-2 and CXCR-2, respectively. The level of IL-1β, IL-6, TNF-α, PD-L1, Arg-1 and iNOS were tested by ELISA. Meanwhile, the expression of CD33+ was tested by flow cytometry. The expression of CXCL-2 and CXCR-2 in NPC cells was higher, compared to that in NP69 cells. In contrast, SPLUNC1 level in NPC cells was much lower than that in NP69 cells. SPLUNC1 level was negatively correlated with CXCL-2 and CXCR-2. Overexpression of SPLUNC1 reversed LPS-induced inflammatory responses and proliferation in NPC cells. In addition, SPLUNC1 upregulation could reverse LPS-induced proliferation of MDSCs in tumor microenvironment. Meanwhile, SPLUNC1 overexpression could regulate CXCL-2/CXCR-2 axis through decreasing CXCL-2 and CXCR-2 protein and mRNA expression. SPLUNC1 regulates LPS-induced progression of nasopharyngeal carcinoma and proliferation of MDSCs. Thus, our study might provide a theoretical basis for discovering new strategies against NPC.

Immunotherapy of targeting MDSCs in tumor microenvironment.

Myeloid-derived suppressor cells (MDSCs) are a group of heterogeneous cells which are abnormally accumulated during the differentiation of myeloid cells. Immunosuppression is the main functional feature of MDSCs, which inhibit T cell activity in the tumor microenvironment (TME) and promote tumoral immune escape. The main principle for immunotherapy is to modulate, restore, and remodel the plasticity and potential of immune system to have an effective anti-tumor response. In the TME, MDSCs are major obstacles to cancer immunotherapy through reducing the anti-tumor efficacy and making tumor cells more resistant to immunotherapy. Therefore, targeting MDSCs treatment becomes the priority of relevant studies and provides new immunotherapeutic strategy for cancer treatment. In this review, we mainly discuss the functions and mechanisms of MDSCs as well as their functional changes in the TME. Further, we review therapeutic effects of immunotherapy against MDSCs and potential breakthroughs regarding immunotherapy targeting MDSCs and immune checkpoint blockade (ICB) immunotherapy.

Abstract 5542: Characterization of a long-acting IL-13 super-antagonist engineered to target tumor associated macrophages and myeloid cells

Abstract Introduction: Regulation of Th1/Th2 balance in the tumor microenvironment (TME) plays an important role in both tumor progression and response to immunotherapy. The IL-4/IL-13 pathway induces an anti-inflammatory (Th2) response by stimulating M2 skewing of tumor associated macrophage (TAM) and myeloid derived suppressor cells (MDSCs), thereby supporting tumor growth by suppressing Th1 response. Therefore, inhibition of the IL-4/IL-13 pathway has the potential to inhibit tumor growth by shifting the TME towards a pro-inflammatory response. To achieve this, we engineered a long-acting IL-13 super-antagonist (i.e., Fc-MDNA413) to target the IL-13Rα1 component of type II IL-4 receptor (IL-4Rα/IL-13α1) expressed on TAMs and MDSCs to inhibit their differentiation and expansion for immuno-oncological applications. Experimental Procedure: Studies conducted include binding analyses by Biacore/SPR, signaling analyses in IL-4/IL-13 cell reporters, in vitro cell proliferation, in vitro M1/M2 macrophage polarization and in vivo efficacy in syngeneic tumor models. Summary of Data: IL-13Rα1 and IL-4Rα constitute the type II IL-4R that drives a Th2 response upon activation by IL-4 and IL-13. Binding studies showed that in comparison to wild-type Fc-IL13, Fc-MDNA413 has higher affinity for IL-13Rα1 but lower affinity for the decoy IL-13Rα2 receptor, indicating a more favorable receptor selectivity. In a cell-based reporter assay, Fc-MDNA413 inhibits both IL-4 and IL-13 induced p-STAT6 signaling, a pathway that drives towards a Th2 response. The antagonism of Fc-MDNA413 was also observed in an IL-13 dependent TF-1 proliferation assay where dose-dependent inhibition of cell proliferation was demonstrated. In a macrophage polarization assay with human primary myeloid cells, Fc-MDNA413 inhibited both IL-4 and IL-13 induced M2 polarization in a dose-dependent manner, consistent with an inhibitory effect on IL-4/IL-13 signaling. Treatment of tumor bearing mice with Fc-MDNA413 inhibited tumor growth in multiple syngeneic tumor models (e.g., EMT6 breast cancer and KLN205 lung cancer) known to have higher percentage of TAMs and MDSCs in TME, hence demonstrating the therapeutic potential of this long-acting IL-4/IL-13 super-antagonist. Conclusion: Fc-MDNA413 is a long-acting IL-4/IL-13 super-antagonist that inhibits IL-4 and IL-13 induced signaling and M2 skewing of macrophages, resulting in tumor growth inhibition in vivo. Ongoing studies include testing in additional syngeneic tumor models, deciphering in vivo mechanism of action and investigating potential synergy with other therapies. Next generation multifunctional superkines that incorporate IL-4/IL-13 antagonism are under development to target immunologically challenging tumors. Citation Format: Aanchal Sharma, Manjunatha Ankathatti Munegowda, Fahar Merchant, Minh D. To. Characterization of a long-acting IL-13 super-antagonist engineered to target tumor associated macrophages and myeloid cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5542.

Semaphorin 4B promotes tumor progression and associates with immune infiltrates in lung adenocarcinoma.

BackgroundSemaphorins have been found to play important roles in multiple malignancy-related processes. However, the role of Semaphorin 4B (SEMA4B) in lung cancer remains unclear. Here, we aimed to explore the biological functions of SEMA4B in through bioinformatic analysis, in vitro and in vivo assays. In the present study, the possible mechanism by which SEMA4B affected the tumor growth and microenvironment of lung adenocarcinoma (LUAD) were investigated.MethodsThe expression of SEMA4B in LUAD was analyzed by bioinformatic analysis and verified by the immunohistochemistry staining. The prognostic value of SEMA4B in LUAD was investigated using the Kaplan-Meier survival and Cox’s regression model. After silencing SEMA4B expression, the functions of SEMA4B in LUAD cells were investigated by in vitro experiments, including CCK-8 and plate clone formation. And the effect of SEMA4B on tumor growth and immune infiltration was explored in C57BL/6 mice tumor-bearing models.ResultsSEMA4B expression was upregulated in LUAD tissues and correlated with later pathological stages and poor prognosis of LUAD patients. Further study found that SEMA4B silencing suppressed the proliferation of lung cancer cells both in vitro and in vivo. Bioinformatic analysis showed that SEMA4B expression was correlated with the increased infiltration of myeloid-derived suppressor cells (MDSCs), T-regs and the decreased infiltration of CD8+ T cell in LUAD. Importantly, in vivo study verified that the infiltration of T-regs and MDSCs in tumor microenvironment (TME) of Xenograft tissues was decreased after SEMA4B silencing.ConclusionsThese findings demonstrated SEMA4B might play an oncogenic role in LUAD progression, and be a promising therapeutic target for lung cancer.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12885-022-09696-w.

MicroRNAs/LncRNAs Modulate MDSCs in Tumor Microenvironment.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immature cells derived from bone marrow that play critical immunosuppressive functions in the tumor microenvironment (TME), promoting cancer progression. According to base length, Non-coding RNAs (ncRNAs) are mainly divided into: microRNAs (miRNAs), lncRNAs, snRNAs and CircRNAs. Both miRNA and lncRNA are transcribed by RNA polymerase II, and they play an important role in gene expression under both physiological and pathological conditions. The increasing data have shown that MiRNAs/LncRNAs regulate MDSCs within TME, becoming one of potential breakthrough points at the investigation and treatment of cancer. Therefore, we summarize how miRNAs/lncRNAs mediate the differentiation, expansion and immunosuppressive function of tumor MDSCs in TME. We will then focus on the regulatory mechanisms of exosomal MicroRNAs/LncRNAs on tumor MDSCs. Finally, we will discuss how the interaction of miRNAs/lncRNAs modulates tumor MDSCs.

MicroRNA networks regulate the differentiation, expansion and suppression function of myeloid-derived suppressor cells in tumor microenvironment.

Myeloid-derived suppressor cells (MDSCs), one heterogeneous population of immature myeloid cells, have suppressive function on immune response during tumor, inflammation, infection and autoimmune diseases. The molecular mechanism underlying expansion and function of MDSCs is becoming appreciated to manipulate immune response in the diseases. MicroRNA (miRNAs) as one short noncoding RNAs, are involved in regulating cell proliferation, differentiation and maturation. However, it needs to be further studied how miRNAs mediate the development and function of MDSC in association with cancer and other diseases. In the review, we report and discuss recent studies that miRNAs networks regulate the differentiation, expansion and suppression function of MDSCs in tumor microenvironment or other diseases through different signaling pathways. Those studies may provide one novel potential approach for tumor immunotherapy.

Immune Dysfunction Induced by Myeloid-Derived Suppressor Cells in Lymphoma

Lymphoma cancer cells have strongly orchestrated interactions with immune cells and also other surrounding stromal cells in tumor microenvironment. Myeloid derived suppressor cells (MDSC) is believed to have major role in induction of immune suppressive effects in tumor microenvironment. This heterogeneous population of immature myeloid cells influence on immune cells function by indirectly Treg differentiation and directly oxidative stress induction and nutrient depletion in tumor milieu. Our understanding of the role of MDSCs in tumor microenvironment suggests novel immunotherapeutic approaches and need to be more explored. In this article we briefly discuss the main MDSCs immune dysfunction mechanisms with more focus in lymphoma.

Special Issue on Immune Responses in Tumors and Non-Transformed Inflammatory Microenvironments

Special Issue on Immune Responses in Tumors and Non-Transformed Inflammatory Microenvironments