CD86 is an activation receptor for NK cell cytotoxicity against tumor cells
Yanmeng Peng1, Gaoxing Luo1, Junyi Zhou1
1State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, Third Military Medical University, Chongqing, China ; Chongqing Key Laboratory for Disease, Proteomics, Chongqing, China.
Abstract:
CTLA4Ig has been successfully used in the clinic for suppression of T cell activation. However, patients treated with CTLA4Ig experienced reduced incidence of tumors than predicted, but the underlying mechanism remains unknown. In this paper, we showed that brief administration of CTLA4Ig significantly reduced tumor metastasis and prolonged the survival of host mice bearing B16 melanoma. Depletion of NK cells prior to CTLA4Ig administration eliminated the CTLA4Ig-mediated anti-tumor activity. CTLA4Ig enhanced NK cell cytotoxicity to tumor cells via up-regulation of NK cell effecter molecules CD107a and perforin in vivo. In addition, we demonstrated that, upon activation, NK cells could significantly increase the expression of CD86 both in vitro and in vivo, and ligation of CD86 with CTLA4Ig significantly increased the ability of NK cells to kill tumor cells. Furthermore, a human NK cell line that expressed high level of CD86 was directly activated by CTLA4Ig so that killing of tumor targets was enhanced; this enhanced killing could be inhibited by blocking CD86. Our findings uncover a novel function of CTLA4Ig in tumor immunity and suggest that CD86 on NK cells is an activating receptor and closely involved in the CTLA4Ig-mediated anti-tumor response.
Insights
Cytotoxic T-Lymphocyte-Associated protein 4-Ig (CTLA4Ig) enhances natural killer (NK) cell anti-tumor activity by up-regulating CD86. This reveals a new mechanism for CTLA4Ig in cancer immunity.
Area of Science:
- Immunology
- Cancer Research
- Molecular Biology
Background:
- Cytotoxic T-Lymphocyte-Associated protein 4-Ig (CTLA4Ig) is clinically used to suppress T cell activation.
- Observed reduced tumor incidence in patients treated with CTLA4Ig, but the mechanism was unclear.
- CTLA4Ig's role in tumor immunity beyond T cell suppression needed investigation.
Purpose of the Study:
- To investigate the underlying mechanism of CTLA4Ig's anti-tumor effects.
- To explore the role of natural killer (NK) cells in CTLA4Ig-mediated anti-tumor responses.
- To determine if CD86 on NK cells is involved in CTLA4Ig's function.
Main Methods:
- Administration of CTLA4Ig to mice bearing B16 melanoma.
- Depletion of NK cells to assess their role in CTLA4Ig's anti-tumor activity.
- Analysis of NK cell effector molecules (CD107a, perforin) and CD86 expression.
- In vitro and in vivo experiments using NK cells and tumor cells, including blocking CD86.
Main Results:
- CTLA4Ig administration significantly reduced tumor metastasis and prolonged survival in mice.
- Anti-tumor activity of CTLA4Ig was dependent on the presence of NK cells.
- CTLA4Ig enhanced NK cell cytotoxicity by up-regulating CD107a and perforin.
- Activated NK cells increased CD86 expression, and CTLA4Ig ligation of CD86 enhanced NK cell tumor-killing ability.
Conclusions:
- CTLA4Ig possesses a novel function in tumor immunity mediated by NK cells.
- CD86 on NK cells acts as an activating receptor involved in CTLA4Ig's anti-tumor response.
- Targeting the CTLA4Ig-CD86 interaction on NK cells could be a therapeutic strategy.
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