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Soluble CD146 Cooperates with VEGFa to Generate an Immunosuppressive Microenvironment in CD146-Positive Tumors:
Ahmad Joshkon1,2, Wael Traboulsi1, Magali Terme3
1Aix-Marseille Univ, INSERM1263, INRAE1260, C2VN, Marseille, France.
Abstract:
Tumor development necessitates immune escape through different mechanisms. To counteract these effects, the development of therapies targeting immune checkpoints (ICP) has generated interest as they have produced lasting objective responses in patients with advanced metastatic tumors. However, many tumors do not respond to inhibitors of ICPs, necessitating to further study the underlying mechanisms of exhaustion. VEGFa, a proangiogenic molecule secreted by tumors, was described to participate to tumor immune exhaustion by increasing ICPs, justifying in part the use of an anti-VEGFa mAb, bevacizumab, in patients. However, recent studies from our group have demonstrated that tumors can escape anti-VEGFa therapy through the secretion of soluble CD146 (sCD146). In this study, we show that both VEGFa and sCD146 cooperate to create an immunosuppressive microenvironment by increasing the expression of ICPs. In addition, sCD146 favors protumoral M2-type macrophages and induces the secretion of proinflammatory cytokines. An anti-sCD146 mAb reverses these effects and displays additive effects with the anti-VEGFa antibody to eliminate tumors in a syngeneic murine model grafted with melanoma cells. Combining bevacizumab with mucizumab could thus be of major therapeutic interest to prevent immune escape in malignant melanoma and other CD146-positive tumors.
Insights
Tumor cells evade immune attack by increasing immune checkpoints (ICPs). Both VEGFa and soluble CD146 (sCD146) promote ICPs and create an immunosuppressive tumor microenvironment, driving immune escape.
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Tumor development involves immune escape mechanisms, leading to the exploration of immune checkpoint inhibitors (ICPs).
- Vascular Endothelial Growth Factor A (VEGFa) contributes to immune exhaustion by upregulating ICPs, supporting the use of anti-VEGFa therapy like bevacizumab.
- Tumors can develop resistance to anti-VEGFa therapy through the secretion of soluble CD146 (sCD146).
Purpose of the Study:
- To investigate the combined role of VEGFa and sCD146 in promoting an immunosuppressive tumor microenvironment.
- To evaluate the therapeutic potential of targeting sCD146, alone and in combination with anti-VEGFa therapy, in preclinical cancer models.
Main Methods:
- Assessed the impact of VEGFa and sCD146 on immune checkpoint expression in a tumor model.
- Investigated the effects of sCD146 on macrophage polarization and cytokine secretion.
- Evaluated the efficacy of an anti-sCD146 monoclonal antibody (mAb) and bevacizumab in a syngeneic murine melanoma model.
Main Results:
- VEGFa and sCD146 synergistically increase immune checkpoint expression, fostering an immunosuppressive microenvironment.
- sCD146 promotes M2-type macrophages and enhances the secretion of pro-inflammatory cytokines.
- An anti-sCD146 mAb reversed these immunosuppressive effects and showed additive tumor elimination when combined with bevacizumab.
Conclusions:
- VEGFa and sCD146 cooperate to drive tumor immune escape.
- Targeting sCD146 with an antibody, particularly in combination with anti-VEGFa therapy, demonstrates significant therapeutic promise for malignant melanoma and other CD146-positive tumors.
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02:17The Tumor Microenvironment