Sema4a, a member of the semaphorin family, was initially recognized as an axon guidance factor in the nervous system. It is preferentially expressed on immune cells and has 4 types of receptors: Plexin D family, Plexin B family, Tim-2, and Nrp-1. Sema4a plays crucial roles in multiple physiological and pathogenic processes such as cell-cell interactions, immune-cell activation, differentiation, migration, angiogenesis, and carcinogenesis [4].

In prostate cancer, Sema4a was found to be highly expressed. In vivo experiments using mice injected with Sema4a-overexpressing cells showed more dissemination, and genetic depletion of Sema4a prevented lung metastasis in PCa xenograft models, indicating its role in promoting cancer invasion through establishing a positive loop with IL-10 in stromal cells and inducing epithelial-mesenchymal transition of PCa cells [1]. In the context of multiple sclerosis, approximately one-third of patients have high Sema4a levels. Administration of Sema4a concurrently with IFN-β abrogated the efficacy of IFN-β in mouse models of experimental autoimmune encephalomyelitis. Sema4a-deficient (Sema4a KO) recipient mice receiving Th17-skewed myelin oligodendrocyte glycoprotein-specific encephalitogenic T cells had a reduced clinical score, suggesting Sema4a is involved in accelerating Th17-cell-mediated neuroinflammation in the effector phase [2,3,6]. In non-small cell lung cancer, Sema4a-positive tumors responded better to anti-programmed cell death 1 (PD-1) antibody, and Sema4a promoted cytotoxicity and proliferation of tumor-specific CD8+ T cells in murine models [5].

In conclusion, Sema4a is a multifunctional protein involved in various biological processes and diseases. Gene knockout mouse models have been instrumental in revealing its role in promoting cancer invasion in prostate and non-small cell lung cancers, as well as in accelerating neuroinflammation in multiple sclerosis-related models. These findings provide potential therapeutic targets and insights into disease mechanisms.

References:

1. Liu, Xiao, Tan, Weiwei, Wang, Weiqi, Wang, Lin, Zhou, Wei. 2023. SEMA4A promotes prostate cancer invasion: involvement of tumor microenvironment. In Journal of Cancer, 14, 2633-2643. doi:10.7150/jca.86739. https://pubmed.ncbi.nlm.nih.gov/37779872/

2. Nakatsuji, Yuji. . [Sema4A as a biomarker predicting responsiveness to IFN β treatment]. In Rinsho shinkeigaku = Clinical neurology, 54, 972-4. doi:. https://pubmed.ncbi.nlm.nih.gov/25519959/

3. Koda, Toru, Namba, Akiko, Kinoshita, Makoto, Mochizuki, Hideki, Okuno, Tatsusada. 2020. Sema4A is implicated in the acceleration of Th17 cell-mediated neuroinflammation in the effector phase. In Journal of neuroinflammation, 17, 82. doi:10.1186/s12974-020-01757-w. https://pubmed.ncbi.nlm.nih.gov/32169103/

4. Ito, Daisuke, Kumanogoh, Atsushi. 2016. The role of Sema4A in angiogenesis, immune responses, carcinogenesis, and retinal systems. In Cell adhesion & migration, 10, 692-699. doi:. https://pubmed.ncbi.nlm.nih.gov/27736304/

5. Naito, Yujiro, Koyama, Shohei, Masuhiro, Kentaro, Takeda, Yoshito, Kumanogoh, Atsushi. 2023. Tumor-derived semaphorin 4A improves PD-1-blocking antibody efficacy by enhancing CD8+ T cell cytotoxicity and proliferation. In Science advances, 9, eade0718. doi:10.1126/sciadv.ade0718. https://pubmed.ncbi.nlm.nih.gov/37205755/

6. Koda, Toru, Okuno, Tatsusada, Takata, Kazushiro, Kumanogoh, Atsushi, Nakatsuji, Yuji. 2014. Sema4A inhibits the therapeutic effect of IFN-β in EAE. In Journal of neuroimmunology, 268, 43-9. doi:10.1016/j.jneuroim.2013.12.014. https://pubmed.ncbi.nlm.nih.gov/24439904/