Hijacking Sexual Immuno-Privilege in GBM-An Immuno-Evasion Strategy

• Published in: International journal of molecular sciences 2021-10, Vol.22 (20), p.10983
• Main Authors: Sharpe, Martyn A, Baskin, David S, Jenson, Amanda V, Baskin, Alexandra M
• Format: Article
• Language: English
• Subjects: androgen; Androgens; Androgens - metabolism; Antigens; Brain cancer; Brain Neoplasms - immunology; Brain Neoplasms - mortality; Brain Neoplasms - pathology; Carrier Proteins - genetics; Carrier Proteins - metabolism; Databases, Factual; Epitopes; estrogen; Estrogens; Estrogens - metabolism; Female; GBM; Gene expression; Genes; Glioblastoma - immunology; Glioblastoma - mortality; Glioblastoma - pathology; HiF; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Immune privilege; Immune response; Immunosuppression; Kaplan-Meier Estimate; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Macrophages; Male; Metastases; microglia; Microglia - immunology; Microglia - metabolism; Nuclear Receptor Subfamily 1, Group F, Member 3 - genetics; Nuclear Receptor Subfamily 1, Group F, Member 3 - metabolism; Patients; Proteins; Reproductive system; Semen; Sperm; Steroids; Suppressor cells; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Testes; Transcriptomes; Tregs; Tumor Microenvironment; Tumor-Associated Macrophages - immunology; Tumor-Associated Macrophages - metabolism; Tumors; Xenoestrogens
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms222010983

Regulatory T-cells (Tregs) are immunosuppressive T-cells, which arrest immune responses to 'Self' tissues. Some immunosuppressive Tregs that recognize seminal epitopes suppress immune responses to the proteins in semen, in both men and women. We postulated that GBMs express reproductive-associated proteins to manipulate reproductive Tregs and to gain immune privilege. We analyzed four GBM transcriptome databases representing ≈900 tumors for hypoxia-responsive Tregs, steroidogenic pathways, and sperm/testicular and placenta-specific genes, stratifying tumors by expression. In silico analysis suggested that the presence of reproductive-associated Tregs in GBM tumors was associated with worse patient outcomes. These tumors have an androgenic signature, express male-specific antigens, and attract reproductive-associated Related Orphan Receptor C (RORC)-Treg immunosuppressive cells. GBM patient sera were interrogated for the presence of anti-sperm/testicular antibodies, along with age-matched controls, utilizing monkey testicle sections. GBM patient serum contained anti-sperm/testicular antibodies at levels > six-fold that of controls. Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) are associated with estrogenic tumors which appear to mimic placental tissue. We demonstrate that RORC-Tregs drive poor patient outcome, and Treg infiltration correlates strongly with androgen levels. Androgens support GBM expression of sperm/testicular proteins allowing Tregs from the patient's reproductive system to infiltrate the tumor. In contrast, estrogen appears responsible for MDSC/TAM immunosuppression.