Semaphorin-3F is an Immune Suppressor, Not a Tumor Suppressor, in Oral Carcinogenesis

Introduction Secreted Semaphorin-3F (SEMA3F) protein induces repulsion in Neuropilin-2 (NRP2)-expressing cells and guides nervous and circulatory system patterning during embryogenesis. SEMA3F is frequently deleted in human small cell lung cancer and is a potential tumor suppressor gene. SEMA3F is constitutively expressed in epithelial cells in the skin and oral cavity. Recent data from our group has identified NRP2 in CD4+ T cells. Aims Our goal is to investigate the role of endogenous in oral carcinogenesis, tumor progression, and tumor immunity. Methods NRP2 expression was evaluated in progressive stages of oral carcinogenesis. Cancer initiation and progression was analyzed histologically in novel transgenic mice with Sema3Fdeletion in adult keratinocytes before or after exposure to carcinogen compared to controls. Syngeneic oral cancer xenografts were implanted in Nrp2-knockout (KO) or wildtype mice. T cell trafficking in Sema3FKO, K14-Sema3FiKO, Nrp2-KO, and CD4-Nrp2-KO mice were compared to controls during antigen-induced hypersensitivity reactions.. Results was not expressed in normal oral and skin epithelium but upregulated in late dysplasia during carcinogenesis in humans and mice. The majority of control (Sema3F-intact) mice (25/30) developed carcinoma in situ (CIS) or invasive oral squamous cell carcinoma (OSCC) while only 21.7% of K14-Sema3F-KO mice (5/23) developed CIS and none progressed to OSCC. Oral cancer xenografts showed increased CD4+ lymphocyte infiltration in Nrp2 compared to Nrp2 mice. Mice lacking epithelial Sema3F or Nrp2+ T cells showed enhanced and prolonged inflammation, tissue swelling, and T cell infiltration while control mice resolved quickly. Conclusion Sema3F is not a tumor suppressor in OSCC because the epithelium lacks Nrp2 expression and deletion of Sema3Freduced carcinogenesis. Cancerous and inflamed tissues lacking Sema3F or Nrp2 increased immune surveillance and lymphocyte recruitment abrogating cancer initiation and preventing oral cancer progression. The SEMA3F/NRP2 pathway suppresses host immunity and provides new targets for immunotherapy in oral cancer.