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Published on: November 28, 2019
In vivo CD40 ligation can induce T-cell-independent antitumor effects that involve macrophages
Hillary D Lum1, Ilia N Buhtoiarov, Brian E Schmidt
1Department of Human Oncology, University of Wisconsin, Madison, WI 53792, USA.
Abstract:
We have previously demonstrated T cell-independent antitumor and antimetastatic effects of CD40 ligation that involved natural killer (NK) cells. As CD40 molecules are expressed on the surface of macrophages (Mphi), we hypothesized that Mphi may also serve as antitumor effector cells when activated by CD40 ligation. Progression of subcutaneous NXS2 murine neuroblastomas was delayed significantly by agonistic CD40 monoclonal antibody (anti-CD40 mAb) therapy in immunocompetent A/J mice, as well as in T and B cell-deficient severe combined immunodeficiency (SCID) mice. Although NK cells can be activated by anti-CD40 mAb, anti-CD40 mAb treatment also induced a significant antitumor effect in SCID/beige mice in the absence of T and NK effector cells, even when noncytolytic NK cells and polymorphonuclear cells (PMN) were depleted. Furthermore, in vivo treatment with anti-CD40 mAb resulted in enhanced expression of cytokines and cell surface activation markers, as well as Mphi-mediated tumor inhibition in A/J mice, C57BL/6 mice, and SCID/beige mice, as measured in vitro. A role for Mphi was shown by reduction in the antitumor effect of anti-CD40 mAb when Mphi functions were inhibited in vivo by silica. In addition, activation of peritoneal Mphi by anti-CD40 mAb resulted in survival benefits in mice bearing intraperitoneal tumors. Taken together, our results show that anti-CD40 mAb immunotherapy of mice can inhibit tumor growth in the absence of T cells, NK cells, and PMN through the involvement of activated Mphi.
Insights
CD40 ligation using an antibody therapy effectively delays tumor growth by activating macrophages (Mphi). This immunotherapy works even without T cells, NK cells, or PMNs, highlighting Mphi as key antitumor effectors.
Area of Science:
- Immunology
- Cancer Research
- Cell Biology
Background:
- CD40 ligation previously showed T cell-independent antitumor effects involving natural killer (NK) cells.
- CD40 is expressed on macrophages (Mphi), suggesting their potential role in CD40-mediated antitumor responses.
Purpose of the Study:
- To investigate the hypothesis that Mphi act as antitumor effector cells upon CD40 ligation.
- To determine the role of Mphi in the antitumor effects of anti-CD40 monoclonal antibody (mAb) therapy.
Main Methods:
- Administered agonistic anti-CD40 mAb to immunocompetent and severe combined immunodeficiency (SCID) mice bearing NXS2 neuroblastomas.
- Assessed tumor progression, cytokine expression, and cell surface activation markers.
- Inhibited Mphi function using silica to evaluate their contribution to the antitumor effect.
- Activated peritoneal Mphi in mice with established intraperitoneal tumors.
Main Results:
- Anti-CD40 mAb therapy significantly delayed tumor progression in various mouse models, including SCID mice lacking T and B cells.
- Significant antitumor effects were observed even in SCID/beige mice lacking T cells, NK cells, and polymorphonuclear cells (PMNs).
- In vivo anti-CD40 mAb treatment enhanced Mphi activation, cytokine production, and Mphi-mediated tumor inhibition, confirmed by silica treatment reducing efficacy.
- Mphi activation by anti-CD40 mAb led to survival benefits in mice with intraperitoneal tumors.
Conclusions:
- CD40 ligation via anti-CD40 mAb immunotherapy mediates significant antitumor effects independently of T cells, NK cells, and PMNs.
- Activated macrophages (Mphi) are crucial effector cells in anti-CD40 mAb immunotherapy, driving tumor growth inhibition.
- This study establishes Mphi as key players in CD40-targeted cancer immunotherapy.
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