Importance of semaphorins in cancer immunity

The semaphorin family is characterized by the presence of a sema domain and plexin-semaphorin integrin domains. Although, when they were first discovered, semaphorins were reported for their axon-guidance ability (1), recent studies indicate that semaphorins regulate several hallmarks of cancer (2-4). For example, semaphorin 3A (SEMA3A) reduced tumor growth and angiogenesis through upregulating the forkhead box O3a (FOXO3a) dependent, melanoma cell adhesion molecule (MelCAM) in breast cancer in xenograft NOD-SCID mouse model (5). SEMA3B was found to inhibit tumor growth, while increasing metastatic dissemination by activating the p38-MAPK-p21 pathway in immunocompromised CD1^–/– nude athymic female mice (6). SEMA6A employed the FAS-associated death domain protein (FADD) and heme oxygenase 1 (HMOX1) to suppress survival and migration, respectively, in lung cancer cells (7,8). Moreover, the high expression of SEMA6D in the Tie-2 expressing monocyte subset within the tumor suggests that SEMA6D might induce angiogenesis by PlexinB1 or vascular endothelial growth factor receptor (VEGFR) signalling (9).

Researchers have recently recognized semaphorins’ ability to influence immune responses in cancer, in addition to their effects on survival, metastasis, and angiogenesis in cancer cells. It is not surprising that semaphorins modulate immunity in cancer, since several members of the semaphorin family demonstrate a regulatory function in the immune system. SEMA3A, SEMA3B, and SEMA4D demonstrate the potential to induce tumor-associated macrophages that reduce anti-cancer immunity (10-14). SEMA3E, SEMA6D, and SEMA7A enhance the activities of T cells, monocytes, dendritic cells, or B cells (10,15). On the other hand, SEMA3A is one of the well-known immune suppressors, which has been reported to inhibit T cell proliferation (16) and to maintain the activity of T regulatory (Treg) cells by binding to the neuropilin 1 (NRP1) receptor (13). SEMA4A also supported survival of Treg cells via NRP1 binding (14).

Genes, such as cytotoxic T lymphocyte-associated antigen-4 (CTLA4), programmed cell death-1 (PD-1), and PD-1 ligand-1 (PD-L1), have been used for immunotherapy in cancer; however, their efficacy is not ideal, and the efficacy varies for different types of cancer. Semaphorins’ extensive functions in immune regulation make them potential candidates for use in immunotherapy treatment for cancer. An anti-SEMA3A antibody was patented for the treatment of Alzheimer's disease and immune dysfunction, including lowering the immune suppression caused by tumor-secreted SEMA3A (US9879075B2). Also patented is a SEMA4D inhibitor to increase the frequency of a tumor-infiltrating leukocyte by blocking the binding of SEMA4D and its receptor (US9243068B2). Moreover, a phase 1b/2 study reported that Pepinemab (VX15/2503), a humanized IgG4 monoclonal antibody against SEMA4D, showed initial signals of antitumor activity in combination with avelumab in advanced non-small cell lung cancer (17). Furthermore, some patents focus on the receptors of semaphorins, such as PlexinD1 (US9422358B2) and NRP1 (US9540439B2), to promote anti-cancer immunity. Thus, semaphorins seem to be a rising star in immunotherapy treatment of cancer.

Currently, only a few semaphorins show promise in regulating anti-cancer immunity. However, the immune regulatory effects of most semaphorins are demonstrated in other diseases. For example, SEMA5A and SEMA7A are involved in the pathogenesis of rheumatoid arthritis by promoting activities of T cells (18). Research suggests that SEMA3E plays an important role in modulating immune responses to prevent allergic asthma (19). Furthermore, some semaphorins, whose receptors have the ability to regulate immunity when binding with other semaphorins, have not been investigated for their function in the immune system. Therefore, the knowledge of semaphorins in anti-cancer immunity is in its infancy, and more effort should be invested to understand utilizing semaphorins in cancer immunotherapy in the future.

In conclusion, evidence that semaphorins play important roles in immune regulation is increasing; however, there is still very little knowledge of the use of semaphorins in cancer immunity. The valuable study of the function of semaphorins in cancer immunity and immunotherapy should be expanded.

Acknowledgments

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the working ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

References

1. Kolodkin AL, Matthes DJ, O'Connor TP, et al. Fasciclin IV: sequence, expression, and function during growth cone guidance in the grasshopper embryo. Neuron 1992;9:831-45. [Crossref] [PubMed]
2. Arese M, Bussolino F, Pergolizzi M, et al. Tumor progression: the neuronal input. Ann Transl Med 2018;6:89. [Crossref] [PubMed]
3. Butti R, Kumar TV, Nimma R, et al. Impact of semaphorin expression on prognostic characteristics in breast cancer. Breast Cancer (Dove Med Press) 2018;10:79-88. [Crossref] [PubMed]
4. Fan M, Yang L, Li F, et al. Axon guidance repulsant SEMA3F increases chemosensitivity to oxaliplatin and inhibits epithelial-mesenchymal transition of colorectal cancer cells. Transl Cancer Res 2017;6:206-17. [Crossref]
5. Mishra R, Thorat D, Soundararajan G, et al. Semaphorin 3A upregulates FOXO 3a-dependent MelCAM expression leading to attenuation of breast tumor growth and angiogenesis. Oncogene 2015;34:1584-95. [Crossref] [PubMed]
6. Rolny C, Capparuccia L, Casazza A, et al. The tumor suppressor semaphorin 3B triggers a prometastatic program mediated by interleukin 8 and the tumor microenvironment. J Exp Med 2008;205:1155-71. [Crossref] [PubMed]
7. Shen CY, Chang YC, Chen LH, et al. The extracellular SEMA domain attenuates intracellular apoptotic signaling of semaphorin 6A in lung cancer cells. Oncogenesis 2018;7:95. [Crossref] [PubMed]
8. Chen LH, Liao CY, Lai LC, et al. Semaphorin 6A attenuates the migration capability of lung cancer cells via the NRF2/HMOX1 axis. Sci Rep 2019;9:13302. [Crossref] [PubMed]
9. Pucci F, Venneri MA, Biziato D, et al. A distinguishing gene signature shared by tumor-infiltrating Tie2-expressing monocytes, blood "resident" monocytes, and embryonic macrophages suggests common functions and developmental relationships. Blood 2009;114:901-14. [Crossref] [PubMed]
10. Catalano A, Caprari P, Moretti S, et al. Semaphorin-3A is expressed by tumor cells and alters T-cell signal transduction and function. Blood 2006;107:3321-9. [Crossref] [PubMed]
11. Yamamoto M, Suzuki K, Okuno T, et al. Plexin-A4 negatively regulates T lymphocyte responses. Int Immunol 2008;20:413-20. [Crossref] [PubMed]
12. Mantovani A, Sica A. Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Curr Opin Immunol 2010;22:231-7. [Crossref] [PubMed]
13. Casazza A, Laoui D, Wenes M, et al. Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity. Cancer Cell 2013;24:695-709. [Crossref] [PubMed]
14. Delgoffe GM, Woo SR, Turnis ME, et al. Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4a axis. Nature 2013;501:252-6. [Crossref] [PubMed]
15. Roney K, Holl E, Ting J. Immune plexins and semaphorins: old proteins, new immune functions. Protein Cell 2013;4:17-26. [Crossref] [PubMed]
16. Lepelletier Y, Moura IC, Hadj-Slimane R, et al. Immunosuppressive role of semaphorin-3A on T cell proliferation is mediated by inhibition of actin cytoskeleton reorganization. Eur J Immunol 2006;36:1782-93. [Crossref] [PubMed]
17. Shafique MR, Fisher TL, Evans EE, et al. Preliminary results from CLASSICAL-Lung, a phase 1b/2 study of pepinemab (VX15/2503) in combination with avelumab in advanced NSCLC. J Clin Oncol 2019;37:2601. [Crossref]
18. Nishide M, Kumanogoh A. The role of semaphorins in immune responses and autoimmune rheumatic diseases. Nat Rev Rheumatol 2018;14:19-31. [Crossref] [PubMed]
19. Movassagh H, Koussih L, Shan L, et al. The regulatory role of semaphorin 3E in allergic asthma. Int J Biochem Cell Biol 2019;106:68-73. [Crossref] [PubMed]