Antitumor Effects of Anti-Semaphorin 4D Antibody Unravel a Novel Proinvasive Mechanism of Vascular-Targeting Agents

Abstract

Binding of the vascular-targeting agent anti-Sema4D to Sema4D on macrophages promotes a malignant phenotype via SDF1/CXCR4 signaling.One of the main consequences of inhibition of neovessel growth and vessel pruning produced by angiogenesis inhibitors is increased intratumor hypoxia. Growing evidence indicates that tumor cells escape from this hypoxic environment to better nourished locations, presenting hypoxia as a positive stimulus for invasion. In particular, anti-VEGF/R therapies produce hypoxia-induced invasion and metastasis in a spontaneous mouse model of pancreatic neuroendocrine cancer (PanNET), RIP1-Tag2. Here, a novel vascular-targeting agent targeting semaphorin 4D (Sema4D) demonstrated impaired tumor growth and extended survival in the RIP1-Tag2 model. Surprisingly, although there was no induction of intratumor hypoxia by anti-Sema4D therapy, the increase in local invasion and distant metastases was comparable with the one produced by VEGFR inhibition. Mechanistically, the antitumor effect was due to an alteration in vascular function by modification of pericyte coverage involving platelet-derived growth factor B. On the other hand, the aggressive phenotype involved a macrophage-derived Sema4D signaling engagement, which induced their recruitment to the tumor invasive fronts and secretion of stromal cell-derived factor 1 (SDF1) that triggered tumor cell invasive behavior via CXCR4. A comprehensive clinical validation of the targets in different stages of PanNETs demonstrated the implication of both Sema4D and CXCR4 in tumor progression. Taken together, we demonstrate beneficial antitumor and prosurvival effects of anti-Sema4D antibody but also unravel a novel mechanism of tumor aggressivity. This mechanism implicates recruitment of Sema4D-positive macrophages to invasive fronts and their secretion of proinvasive molecules that ultimately induce local tumor invasion and distant metastasis in PanNETs.

Multi-Omics Profiling Identifies Risk Hypoxia-Related Signatures for Ovarian Cancer Prognosis

“…The hypoxic microenvironment plays a key role in tumorigenesis, radiotherapy, and chemotherapy resistance in OC ( 8 , 9 ). Particularly, hypoxia affects the tumor microenvironment and promotes tumor angiogenesis, the release of damage-associated pattern molecules, tumor immunosuppression, and immune escape ( 10 , 11 ). Hypoxia is also vital in the natural anti-tumor immune response as it can reduce the activity of NK or CTL cells ( 12 ).…”

The Landscape and Clinical Application of the Tumor Microenvironment in Gastroenteropancreatic Neuroendocrine Neoplasms

“…Furthermore, these vasculature factors also influence other cells and molecules in the TME. Semaphorin 4D, which takes advantage of platelet-derived growth factor B to modify pericyte coverage, induces and recruits macrophages in invasive tumor fronts to secrete stromal cell-derived factor 1, thus communicating with tumor cells in which CXCR4 promotes tumor invasion and metastasis in pancreatic NETs [ 88 ]. Periostin, which regulates VEGFA and fibroblast growth factor 2-adaptive alterations for revascularization, is related to M2-like macrophages and exhausts macrophages under a colony-stimulating factor one receptor antibody in pancreatic NETs, revealing how VEGFA might have an immunosuppressive function in addition to angiogenic activity [ 89 ].…”

Semaphorins as Potential Immune Therapeutic Targets for Cancer

“…It indicated that targeting Sema4D might be able to bring favorable prognosis for gastric patients. However, anti-Sema4D treatment with a specific antibody (Mab67, Vaccinex) shrank tumor bulk and improved survival rates in pancreatic neuroendocrine cancer (RIP1-Tag2) mice in a short period, but conversely promoted lymph node metastasis consistent with an increase in TAMs after anti-Sema4D treatment (49). To further identify the mechanism of TAMs promoting metastasis, the study of Oriol Casanovas found a significant increase in stromal cell-derived factor 1 (SDF1, CXCL12, a proinvasive molecule) after anti-Sema4D treatment through a mouse cytokine array.…”