Abstract
The tumor microenvironment (TME) is a complex and heterogeneous environment composed of cancer cells, tumor stroma, a mixture of tissue-resident and infiltrating immune cells, secreted factors, and extracellular matrix proteins. Natural killer (NK) cells play a vital role in fighting tumors, but chronic stimulation and immunosuppression in the TME lead to NK cell exhaustion and limited antitumor functions. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of myeloid cells with potent immunosuppressive activity that gradually accumulate in tumor tissues. MDSCs interact with innate and adaptive immune cells and play a crucial role in negatively regulating the immune response to tumors. This review discusses MDSC-mediated NK cell regulation within the TME, focusing on critical cellular and molecular interactions. We review current strategies that target MDSC-mediated immunosuppression to enhance NK cell cytotoxic antitumor activity. We also speculate on how NK cell-based antitumor immunotherapy could be improved.
Highlights
Tumorigenesis is a complex and dynamic process involving three stages: initiation, progression, and metastasis [1]
The remaining 10% of natural killer (NK) cells are CD56bright CD16dim and reside in the lymphoid tissue; they are considered “immature or unlicensed.”. These NK cells are more sensitive to cytokine stimulation, which will activate the secretion of a variety of cytokines, including interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNFα), IL-5, IL-10, and IL-13 [37,38,39]
The combination of TH-302 therapy with anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed death (PD)-1 cured more than 80% of tumors in a mouse prostate cancer model by reducing Myeloid-derived suppressor cells (MDSCs) and granulocytic subsets and driving T cell migration into the hypoxic tumor sites [400]
Summary
The tumor microenvironment (TME) is a complex and heterogeneous environment composed of cancer cells, tumor stroma, a mixture of tissue-resident and infiltrating immune cells, secreted factors, and extracellular matrix proteins. Natural killer (NK) cells play a vital role in fighting tumors, but chronic stimulation and immunosuppression in the TME lead to NK cell exhaustion and limited antitumor functions. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of myeloid cells with potent immunosuppressive activity that gradually accumulate in tumor tissues. MDSCs interact with innate and adaptive immune cells and play a crucial role in negatively regulating the immune response to tumors. This review discusses MDSC-mediated NK cell regulation within the TME, focusing on critical cellular and molecular interactions. We review current strategies that target MDSC-mediated immunosuppression to enhance NK cell cytotoxic antitumor activity.
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