Targeting Semaphorin 4D in Cancer: A Look from Different Perspectives
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Published on: December 26, 2016
Luca Tamagnone1,2, Giulia Franzolin3,4
1Istituto di Istologia ed Embriologia, Università Cattolica del Sacro Cuore, Rome, Italy. luca.tamagnone@unicatt.it.
Abstract:
Semaphorin 4D (Sema4D) plays a role in various cell types including B lymphocytes, differentiating neurons, endothelial cells, and cancer cells. Preclinical and in vitro studies have shown that Sema4D-directed antibodies in combination with immune checkpoint inhibitors reshape the tumor microenvironment by promoting recruitment of effector lymphocytes and antigen-presenting cells, while reducing immunosuppressive cell types, which ultimately leads to tumor rejection. Hence, early-stage clinical trials with combination therapies including anti-Sema4D antibodies are ongoing. In this issue of Cancer Research, Zuazo-Gaztelu and colleagues report an unexpected proinvasive effect induced by anti-Sema4D antibodies in a preclinical model of neuroendocrine pancreatic cancer (Rip1-Tag2), mediated by retrograde signaling of transmembrane Sema4D in macrophages, which increases their recruitment to tumors, SDF-1 secretion, and metastasis-promoting phenotype.See related article by Zuazo-Gaztelu et al., p. 5328.
Insights
Anti-Semaphorin 4D (Sema4D) antibodies, expected to fight cancer, unexpectedly promote tumor invasion and metastasis in preclinical models. This occurs through retrograde signaling in macrophages, increasing tumor cell spread.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- Semaphorin 4D (Sema4D) is implicated in various cell functions, including immune responses and cancer.
- Sema4D-targeting antibodies combined with immune checkpoint inhibitors are being investigated for cancer therapy due to their potential to modify the tumor microenvironment.
Purpose of the Study:
- To investigate the effect of anti-Sema4D antibodies in a preclinical model of neuroendocrine pancreatic cancer.
- To elucidate the mechanisms underlying the observed effects of anti-Sema4D antibodies on tumor progression.
Main Methods:
- Utilized a preclinical neuroendocrine pancreatic cancer model (Rip1-Tag2).
- Administered anti-Sema4D antibodies and analyzed their impact on tumor microenvironment and metastasis.
- Investigated retrograde signaling pathways involving Sema4D and macrophages.
Main Results:
- Anti-Sema4D antibodies demonstrated an unexpected proinvasive effect in neuroendocrine pancreatic cancer.
- This effect was mediated by retrograde signaling of transmembrane Sema4D in macrophages.
- Macrophage recruitment to tumors, SDF-1 secretion, and a metastasis-promoting phenotype were increased.
Conclusions:
- Anti-Sema4D antibodies can have detrimental proinvasive effects, contrary to expectations.
- Retrograde Sema4D signaling in macrophages is a key mechanism driving antibody-induced metastasis.
- Findings highlight the complexity of targeting Sema4D in cancer therapy and necessitate further investigation.
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