Exportin 1 governs the immunosuppressive functions of myeloid-derived suppressor cells in tumors through Erk1/2 nuclear export

Rheumatology and Immunology Medicine Cell Biology Biochemistry Oncology Life Sciences Immunology
tumor myeloid-derived suppressor cells Exportin 1 MAPK pathway anti-tumor immunity

Paper Report

Research Background

Myeloid-Derived Suppressor Cells (MDSCs) are a major driving force in tumor immune suppression. Understanding their mechanisms can provide new therapeutic targets to improve anti-tumor immunity, as the development and immunosuppressive function of these cells directly affect anti-tumor immune responses. In preclinical mouse models, studies found that the expression of Exportin 1 (XPO1) is upregulated in tumor MDSCs, induced by IL-6-induced STAT3 activation during MDSC differentiation. Blocking XPO1 can transform MDSCs into neutrophil-like cells that activate T cells, enhancing anti-tumor immune responses and inhibiting tumor growth. This study aims to explore the key role of XPO1 in MDSC differentiation and suppressive function, and to use these findings to provide new therapeutic targets for reprogramming immunosuppressive MDSCs.

Paper Source

This paper was written by Saeed Daneshmandi et al., with research institutions including Roswell Park Comprehensive Cancer Center (USA), Yokohama City University (Japan), etc., published in the journal “Cellular & Molecular Immunology” on June 20, 2024.

Research Process

This study includes multiple steps:

  1. Observation of XPO1 expression in MDSCs and its relationship with STAT3 signaling: The experiment isolated MDSCs from bone marrow and co-cultured them with activated T cells, revealing differences in XPO1 expression and T cell proliferation suppression ability between tumor-bearing and non-tumor-bearing mouse MDSCs.

  2. In vivo and in vitro XPO1 inhibition experiments: Using the XPO1 inhibitor Selinexor to treat mouse tumor models, observing changes in tumor growth and T cell function.

  3. Single-cell transcriptome analysis: Using single-cell RNA sequencing (scRNA-seq) technology to analyze gene expression profile changes in MDSCs after Selinexor treatment, further understanding the impact of XPO1 blockade on MDSC function and differentiation.

  4. Functional analysis: Studying the ability of MDSCs after XPO1 blockade to promote T cell proliferation and anti-tumor effects, evaluating their potential in enhancing immunotherapy efficacy.

  5. In vivo adoptive transfer experiments: Directly observing the impact on tumor model mouse survival rates by infusing Selinexor-treated MDSCs.

Main Research Findings

  1. XPO1 expression in MDSCs is regulated by STAT3 signaling: Experiments verified that IL-6-induced STAT3 signaling significantly upregulates XPO1 expression in MDSCs, mainly through phosphorylated STAT3 at tyrosine 705.

  2. Impact of XPO1 blockade on tumor growth and immunosuppressive function: In EL-4 and C1498 tumor models, blocking XPO1 with Selinexor significantly improved mouse survival rates and slowed tumor growth. Additionally, MDSCs treated with Selinexor showed significantly weakened ability to suppress T cell proliferation, indicating inhibition of their immunosuppressive function.

  3. Single-cell transcriptome analysis reveals the generation of neutrophil-like MDSCs: Through scRNA-seq analysis, it was found that the gene expression profile of MDSCs changed significantly after Selinexor treatment, generating a neutrophil-like subgroup with pro-inflammatory and immunostimulatory functions.

  4. XPO1 blockade inhibits ERK1/2-mediated MAPK signaling pathway: Western blot and co-immunoprecipitation results showed that blocking XPO1 leads to accumulation of ERK1/2 in the nucleus, preventing its phosphorylation and thus inhibiting the activation of the MAPK signaling pathway, thereby reducing the immunosuppressive function of MDSCs.

  5. Clinical relevance analysis and human model validation: Analysis of AML patient datasets showed a negative correlation between XPO1 expression levels and overall survival rates. Simultaneously, Selinexor-treated healthy donor PBMCs showed similar results to the mouse model, indicating consistency in the role of XPO1 in MDSC function in humans.

Research Conclusions and Significance

  1. Scientific value: The study reveals the key role of XPO1 in regulating the differentiation and immunosuppressive function of MDSCs through the ERK1/2-mediated MAPK signaling pathway, providing new insights into understanding tumor immune suppression mechanisms.

  2. Application value: The findings of this paper provide a new intervention target for cancer immunotherapy. XPO1 inhibitors, especially Selinexor, can be used in combination with existing immune checkpoint inhibitors to enhance their therapeutic effects.

  3. Important viewpoints: The research proves that by blocking XPO1, MDSCs can be transformed into neutrophil-like cells with anti-tumor functions, thus breaking the immunosuppressive barrier in the tumor microenvironment and further improving positive treatment responses in cancer patients.

  4. Research highlights: On one hand, this paper reveals the regulatory mechanism of XPO1 in MDSCs for the first time; on the other hand, it demonstrates the potential of XPO1 blockade in practical applications through clinical data and human model validation.

Other Valuable Information

  1. Potential clinical research directions: Future clinical trials can explore the combined application of XPO1 inhibitors with other immunotherapy methods to evaluate their therapeutic effects in various cancer types.

  2. Further research on the ERK pathway: Further research needs to explore the specific mechanisms of ERK1/2 in regulating MDSC function, as well as combination therapy regimens of ERK inhibitors and immune checkpoint inhibitors.

This study not only provides new theoretical basis and practical possibilities for cancer immunotherapy but also points out directions for future related research.