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Complement Receptor 3 Has Negative Impact on Tumor Surveillance through Suppression of Natural Killer Cell Function
Cheng-Fei Liu1, Xiao-Yun Min1, Naiyin Wang2
1Core Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China.
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.
Insights
Complement receptor 3 (CR3) negatively regulates natural killer (NK) cell function, impairing tumor surveillance. Blocking CR3 enhances NK cell anti-tumor activity, suggesting a new therapeutic target for cancer immunotherapy.
Area of Science:
- Immunology
- Cancer Biology
- Cellular Signaling
Background:
- Complement receptor 3 (CR3) is abundant on natural killer (NK) cells, but its role in tumor surveillance is unclear.
- NK cells are crucial for identifying and eliminating tumor cells.
- Dysregulation of NK cell function contributes to tumor progression.
Purpose of the Study:
- To investigate the role of CR3 in NK cell-mediated tumor surveillance.
- To determine if CR3 acts as a negative regulator of NK cell anti-tumor activity.
- To explore the signaling pathways involved in CR3-mediated regulation of NK cells.
Main Methods:
- Utilized CR3-deficient mice (CD11b-/-) and wild-type (WT) mice in a B16-luc melanoma lung metastasis model.
- Performed adaptive transfer of NK cells lacking CR3 into NK-deficient mice.
- Conducted in vitro assays to assess NK cell activity and effector functions upon CR3 engagement with iC3b.
- Analyzed intracellular signaling pathways (SHIP-1, JNK, ERK) in NK cells.
Main Results:
- CR3-deficient mice showed enhanced NK cell activation and improved NK-dependent tumor killing.
- Mice lacking CR3 exhibited reduced tumor growth and metastasis compared to WT mice.
- Transfer of CR3-deficient NK cells resulted in more effective tumor suppression.
- In vitro, iC3b engagement with CR3 on NK cells suppressed their cytotoxic activity and effector functions.
- iC3b stimulation activated SHIP-1 and JNK, while suppressing ERK signaling in NK cells.
Conclusions:
- CR3 acts as a significant negative regulator of NK cell function, hindering tumor surveillance.
- The iC3b/CR3 signaling pathway suppresses NK cell activity, impacting anti-tumor responses.
- Targeting the iC3b/CR3 pathway could enhance NK cell function for cancer therapy.
- This pathway represents a novel target for improving cancer patient outcomes and NK cell-based treatments.
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