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Abstract
Complement receptor 3 (CR3) is expressed abundantly on natural killer (NK) cells; however, whether it plays roles in NK cell-dependent tumor surveillance is largely unknown. Here, we show that CR3 is an important negative regulator of NK cell function, which has negative impact on tumor surveillance. Mice deficient in CR3 (CD11b−/− mice) exhibited a more activated NK phenotype and had enhanced NK-dependent tumor killing. In a B16-luc melanoma-induced lung tumor growth and metastasis model, mice deficient in CR3 had reduced tumor growth and metastases, compared with WT mice. In addition, adaptive transfer of NK cells lacking CR3 (into NK-deficient mice) mediated more efficient suppression of tumor growth and metastases, compared with the transfer of CR3 sufficient NK cells, suggesting that CR3 can impair tumor surveillance through suppression of NK cell function. In vitro analyses showed that engagement of CR3 with iC3b (classical CR3 ligand) on NK cells negatively regulated NK cell activity and effector functions (i.e. direct tumor cell killing, antibody-dependent NK-mediated tumor killing). Cell signaling analyses showed that iC3b stimulation caused activation of Src homology 2 domain-containing inositol-5-phosphatase-1 (SHIP-1) and JNK, and suppression of ERK in NK cells, supporting that iC3b mediates negative regulation of NK cell function through its effects on SHIP-1, JNK, and ERK signal transduction pathways. Thus, our findings demonstrate a previously unknown role for CR3 in dysregulation of NK-dependent tumor surveillance and suggest that the iC3b/CR3 signaling is a critical negative regulator of NK cell function and may represent a new target for preserving NK cell function in cancer patients and improving NK cell-based therapy.
Highlights
Natural killer (NK) cells comprise 2–13% of all circulating lymphocytes and mediate spontaneous killing of tumor, foreign cells, and aberrant host cells by exocytosis of granzyme- and perforincontaining cytoplasmic granules
Tumor cell-induced excessive inflammatory responses can promote the development of immunosuppressive microenvironment leading to compromised NK cell function which enhances tumor growth and metastasis [18,19,20]; current NK cell-based therapy faces a lot of challenges, e.g., functional decline of the reconstituted NK cells in acute myeloid leukemia patients following hematopoietic stem-cell transplantation (HSCT) and rapid loss of cytotoxic activity of infused NK cells that have been expanded ex vivo [21, 22]
Our results indicate that Complement receptor 3 (CR3) signaling negatively regulates NK cell function and impairs NK celldependent tumor surveillance in mice
Summary
Natural killer (NK) cells comprise 2–13% of all circulating lymphocytes and mediate spontaneous killing of tumor, foreign cells, and aberrant host cells by exocytosis of granzyme- and perforincontaining cytoplasmic granules. They produce cytokines (e.g., IFN-γ) to regulate other immune cell functions [1, 2]. In anti-tumor antibody therapy, NK-mediated killing is required for curative efficacy of antibody Together, these observations provide compelling evidence that NK cells play a significant role in tumor surveillance and can be used in therapeutic settings against cancer. More thorough understanding of mechanisms that regulate NK cell function and identifying the mediators that lead to NK dysfunction are required for improvement of NK-based therapy
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