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Tumor-Associated Monocytes/Macrophages Impair NK-Cell Function via TGFβ1 in Human Gastric Cancer
Liu-Sheng Peng1, Jin-Yu Zhang1, Yong-Sheng Teng1
1National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing, PR China.
Abstract:
Natural killer (NK) cells are a major component of the host antitumor immune response in human cancer. However, the nature, functional regulation, and clinical relevance of NK cells in gastric cancer remain largely unknown. In this study, we showed that the percentages of NK cells in tumors were significantly decreased, and low percentages of tumor-infiltrating NK cells were positively correlated with poor survival and disease progression. Although the expression of activating and inhibitory receptors on NK cells was shown to be not different between tumor and nontumor tissues, NK cells in tumors had impaired effector functions, characterized by decreased IFNγ, TNFα, and Ki-67 expression. We found that tumor-infiltrating monocytes/macrophages were physically close to NK cells, and their percentages negatively correlated with IFNγ+ and TNFα+ NK-cell percentages. Ex vivo study showed that isolated tumor-associated monocytes/macrophages could impair NK-cell expression of IFNγ, TNFα, and Ki-67. Blockade of TGFβ1 attenuated such monocytes/macrophages-mediated impairment of NK-cell function. Our data suggest that human NK-cell function was impaired by tumor-associated monocytes/macrophages, and that restoring NK-cell function may be an important therapeutic strategy to prevent tumor immune escape in gastric cancer. Cancer Immunol Res; 5(3); 248-56. ©2017 AACR.
Insights
Natural killer (NK) cells are crucial for fighting gastric cancer but are decreased and functionally impaired within tumors. Tumor-associated monocytes/macrophages suppress NK-cell activity, suggesting a therapeutic target.
Area of Science:
- Immunology
- Oncology
- Cancer Research
Background:
- Natural killer (NK) cells are vital for anti-tumor immunity in human cancers.
- The role and regulation of NK cells in gastric cancer are not well understood.
- NK cell dysfunction is implicated in tumor immune evasion.
Purpose of the Study:
- To investigate the characteristics and function of NK cells in gastric cancer.
- To determine the impact of tumor microenvironment on NK cell activity.
- To explore potential therapeutic strategies targeting NK cells in gastric cancer.
Main Methods:
- Quantification of tumor-infiltrating NK cells and analysis of their receptor expression.
- Assessment of NK cell effector functions (IFNγ, TNFα, Ki-67 expression).
- Co-culture experiments with tumor-associated monocytes/macrophages and blockade of TGFβ1.
Main Results:
- Gastric tumors showed decreased percentages of NK cells, correlating with poor survival.
- Tumor-infiltrating NK cells exhibited impaired effector functions despite normal receptor expression.
- Monocytes/macrophages in close proximity to NK cells suppressed their function, partially mediated by TGFβ1.
Conclusions:
- NK cell function is significantly impaired in the gastric tumor microenvironment by associated monocytes/macrophages.
- Restoring NK cell function represents a promising therapeutic avenue to overcome immune escape in gastric cancer.
- Targeting monocyte/macrophage-mediated suppression could enhance anti-tumor immunity.
