Sema3F Suppresses Tumor Initiation Through Alteration of the Immunological Tumor Microenvironment

SEMA3F is an antilymphangiogenic signaling molecule expressed in the proliferating basal layer of normal epithelium. In orthotopic models of head and neck squamous cell carcinoma, loss of SEMA3F or its receptors results in enhanced tumor growth and locoregional metastasis, leading to speculation that SEMA3F may also prevent cancer initiation. To determine whether the loss of SEMA3F enhances susceptibility to cancer development, we employed a two‐step carcinogenesis model in a robustly immunogenic outbred strain of wild‐type (WT) or Sema3F knockout (KO) mice. Animals were treated with a single application of 7,12‐Dimethylbenz(a)anthracene (DMBA) followed by twice‐weekly applications of 12‐O‐Tetradecanoylphorbol‐13‐acetate (TPA) for 24 weeks. Sema3F KO animals had a modest but statistical decrease in tumor latency compared with WT. Additionally, both the number and size of lesions was significantly decreased in KO animals. Together, this suggested that loss of Sema3F may be influencing cancer development and progression primarily through modulation of the tumor microenvironment. By histochemical staining, KO animals demonstrated much higher percentage of immune infiltrate within the tumors. To investigate whether immunosurveillance may contribute to the diminished cancer progression in KO animals, we analyzed the mRNA expression of inflammatory cytokines from these animals. Analysis of the inflammatory tumor microenvironment in these lesions revealed a strong induction of both IL‐12α and IL‐1β in KO animals. Primarily produced by macrophages, IL‐12α has been shown to suppress the development of skin papillomas and suppress tumor growth and development. Compellingly, macrophages but not leukocytes express Sema3F receptors. Consequently, we propose that expression of Sema3F in the context of chemical carcinogenesis functions as a macrophage chemorepellent and antilymphangiogenic molecule, thus delaying the onset of an adaptive immune response and increasing the latency and tumor burden. Further, Sema3F may be an attractive target for cancer immunotherapies given its autocrine and paracrine signaling roles.Support or Funding InformationThis research was supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research and by Marian University Indianapolis.