Tumor-Associated NK Cells Drive MDSC-Mediated Tumor Immune Tolerance Through the IL-6/STAT3 Axis

Medicine Oncology Life Sciences Immunology
NK cells MDSC tumor immune escape IL-6 STAT3 antigen presentation immune checkpoint inhibition

Tumor-Associated NK Cells Drive MDSC-Mediated Tumor Immune Tolerance via the IL-6/STAT3 Axis — Research by Neo et al.

In recent years, researchers have delved deeply into the mechanisms of tumor immune escape to improve the success rate of cancer immunotherapy. The accumulation of CD8 T cells in the tumor microenvironment is a critical determinant of the response to immune checkpoint therapy, but tumor progression is often accompanied by immune tolerance and the accumulation of immunosuppressive immature myeloid cells (MDSCs). These MDSCs inhibit anti-tumor CD8 T cell responses in various types of cancer, but their biological characteristics are still not fully understood.

Background and Research Purpose

This paper explores the interaction between NK cells and myeloid cells, aiming to reveal how tumor-associated NK cells drive MDSC development through the IL-6/STAT3 pathway, thereby mediating tumor immune escape. Existing research indicates that NK cells are capable of not only surveilling and eliminating virus-infected and cancer-transformed cells, but their functionality and phenotype plasticity also vary in different physiological environments. Studies have shown that NK cells can secrete various cytokines, including GM-CSF and IL-10, which may influence the differentiation of myeloid cells in the tumor microenvironment. However, how NK cells affect the function of myeloid cells through bidirectional interactions remains unclear.

Research Origin

The authors of this paper include Shi Yong Neo, Le Tong, Joni Chong, et al., primarily from the Karolinska Institute, Singapore Immunology Network, and the National University of Singapore. The paper was published in the May 15, 2024, issue of Science Translational Medicine.

Research Process

  1. Gene Signatures and Clinical Relevance Initially, the study used transcriptome deconvolution techniques to analyze patient samples undergoing immune checkpoint therapy, revealing the interaction between NK cells and MDSCs. Through a series of transcriptomics and single-cell transcriptome analyses, the researchers discovered a unique inflammatory gene signature strongly correlated with the NK cell gene signature in non-responders.

  2. Tumor-Experienced NK Cell Phenotype and Immune Regulatory Functions Researchers observed specific phenotypic changes in NK cells after tumor exposure in vitro, including upregulation of CD69 and perforin and the acquisition of immunosuppressive functions. RNA sequencing analysis revealed changes in gene expression during immune activation and differentiation of these tumor-experienced NK cells.

  3. Impact of NK Cells on Myeloid Cells Tumor-experienced NK cells were found to enhance the suppressive function of monocytes and inhibit antigen presentation, thereby affecting the tumor recognition by tumor-infiltrating lymphocytes (TILs). NK cells also enhanced the suppressive capability of neutrophils and maintained them in the tumor microenvironment via induction of the endoplasmic reticulum stress response.

  4. Phenotype Analysis of NK Cells and Myeloid Cells in Patient Tumor Tissues Flow cytometry analysis of tumor tissues from breast cancer and sarcoma patients showed that tumor-infiltrating NK cells could secrete various cytokines, including IL-6, which were strongly correlated with MDSC markers. Further experiments confirmed the key role of IL-6 in NK cell-mediated myeloid cell functions.

  5. Impact on Tumor MHCI Expression In mouse models, researchers found that increased levels of IL-6 in tumors were associated with high MHCI expression, and NK cells exhibited a strong ability to produce IFN-γ in tumors lacking MHCI, thereby weakening the suppressive functions of myeloid cells by affecting the interaction of NK cells.

Research Results

  1. Gene Expression Correlation In tumor samples, the unique inflammatory gene signature showed a strong positive correlation with the NK cell gene signature in immune checkpoint non-responders, particularly significant in melanoma and esophageal cancer patients.

  2. Suppressive NK Cell Phenotype In vitro experiments showed that tumor-exposed NK cells exhibited a CD69+ and perforin- phenotype and secreted pro-inflammatory and immunosuppressive factors, which further inhibited the proliferation of CD8+ T cells.

  3. Impact on Antigen Presentation NK cells could interfere with the antigen-presenting function of monocytes by reducing HLA-DR expression, thereby weakening the recognition of tumors by tumor-infiltrating lymphocytes (TILs).

  4. Neutrophil Survival Maintenance Tumor-associated NK cells maintained the survival and suppressive functions of neutrophils in both in vitro and in vivo experiments by enhancing the endoplasmic reticulum stress response, playing a key role in tumor immune evasion.

  5. Validation of Intercellular Interactions Expression of IL-6 in tumor tissues from breast cancer and sarcoma patients was significantly positively correlated with MDSC markers, further confirming the critical role of NK cells in tumor immune tolerance.

Research Significance

This study unveils the mechanism by which tumor-associated NK cells drive MDSC-mediated tumor immune tolerance via the IL-6/STAT3 axis, providing a new perspective for understanding intercellular interactions in the tumor microenvironment and suggesting potential strategies to regulate NK cell functions in cancer immunotherapy. The results indicate that a high content of NK cells in tumors does not necessarily correlate with a good prognosis; instead, it may promote the formation of immune tolerance. Therefore, future therapeutic strategies should consider regulating NK cell functions to avoid the production of immunosuppressive factors and promote the development and recruitment of dendritic cells, offering new pathways for cancer treatment.

Research Highlights

  1. Revealing the Key Interaction Mechanism Between NK Cells and MDSCs The study validated through various experiments that tumor-associated NK cells regulate myeloid cells via the IL-6/STAT3 axis, promoting tumor immune escape.

  2. Providing New Targets for Precision Therapy By inhibiting the IL-6/STAT3 signaling pathway, immune suppression can be mitigated, enhancing anti-tumor T cell responses and offering new strategies for tumor therapy.

  3. In-depth Understanding of Intercellular Interactions in the Tumor Microenvironment The findings emphasize the complex role of NK cells in immune regulation within the tumor microenvironment, providing new directions for future research.

Through multi-level experimental validation, this study reveals the critical role of tumor-associated NK cells in tumor immune tolerance, providing an important scientific basis and potential therapeutic targets for cancer immunotherapy.