Yu Mei1, Wenya Linda Bi2,3, James Agolia1, Changchen Hu1,4, Alexandra M Giantini Larsen5, David M Meredith6, Sally Al Abdulmohsen1,7, Tejus Bale8, Gavin P Dunn9,10, Malak Abedalthagafi7, Ian F Dunn11. 1. Center for Skull Base and Pituitary Surgery, Department of Neurosurgery, Harvard Medical School, Brigham and Women's Hospital, 60 Fenwood Road, Boston, MA, 02115, USA. 2. Center for Skull Base and Pituitary Surgery, Department of Neurosurgery, Harvard Medical School, Brigham and Women's Hospital, 60 Fenwood Road, Boston, MA, 02115, USA. wbi@bwh.harvard.edu. 3. Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. wbi@bwh.harvard.edu. 4. Department of Neurosurgery, Shanxi Provincial People's Hospital, Shanxi Medical University, Taiyuan, China. 5. Department of Neurosurgery, Weill Cornell Hospital, New York, NY, USA. 6. Department of Pathology, Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA. 7. King Fahad Medical City and King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia. 8. Department of Neuropathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 9. Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, USA. 10. Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, USA. 11. Department of Neurosurgery, University of Oklahoma Health Sciences Center, HHDC Suite 4000, 1000 N. Lincoln Blvd, Oklahoma City, OK, 73104, USA. ian-dunn@ouhsc.edu.
Abstract
PURPOSE: Pituitary tumors are the second most common primary brain tumors. Functional tumors demonstrate increased PD-L1 expression, but expression of other checkpoint regulators has not been characterized. We sought to characterize the immune microenvironment of human pituitary tumors to identify new treatment opportunities. METHODS: 72 pituitary tumors were evaluated for expression of the immune regulatory markers programmed death ligand 1 (PD-L1), programmed death ligand 2 (PD-L2), V-domain Ig suppressor of T cell activation (VISTA), lymphocyte activation gene 3 (LAG3) and tumor necrosis factor receptor superfamily member 4 (OX40) by immunohistochemistry (IHC). Lymphocyte infiltration, macrophage infiltration, and angiogenesis were analyzed using IHC. Expression of pituitary tumor initiating cell marker CD15 and mismatch repair proteins MutS protein homolog 2 (MSH2) and MutS protein homolog 6 (MSH6) was also assessed. RESULTS: Pituitary tumors were infiltrated by macrophages and T cells, and they expressed varying levels of PD-L1, PD-L2, VISTA, LAG3, and OX40. Functional tumors and tumors with high expression of tumor stem cell markers had higher immune cell infiltration and greater expression of immunosuppressive checkpoint regulators. Increased PD-L1 and LAG3 and reduced VISTA were observed in primary tumors compared to recurrent tumors. CONCLUSION: Immune cell infiltration and checkpoint regulator expression vary depending on functional status and presence of pituitary tumor initiating cells. Functional tumors may have a particularly immunosuppressive microenvironment. Further studies of immune checkpoint blockade of pituitary tumors, particularly functional tumors, are warranted, though combination therapy may be required.
PURPOSE: Pituitary tumors are the second most common primary brain tumors. Functional tumors demonstrate increased PD-L1 expression, but expression of other checkpoint regulators has not been characterized. We sought to characterize the immune microenvironment of human pituitary tumors to identify new treatment opportunities. METHODS: 72 pituitary tumors were evaluated for expression of the immune regulatory markers programmed death ligand 1 (PD-L1), programmed death ligand 2 (PD-L2), V-domain Ig suppressor of T cell activation (VISTA), lymphocyte activation gene 3 (LAG3) and tumor necrosis factor receptor superfamily member 4 (OX40) by immunohistochemistry (IHC). Lymphocyte infiltration, macrophage infiltration, and angiogenesis were analyzed using IHC. Expression of pituitary tumor initiating cell marker CD15 and mismatch repair proteins MutS protein homolog 2 (MSH2) and MutS protein homolog 6 (MSH6) was also assessed. RESULTS: Pituitary tumors were infiltrated by macrophages and T cells, and they expressed varying levels of PD-L1, PD-L2, VISTA, LAG3, and OX40. Functional tumors and tumors with high expression of tumor stem cell markers had higher immune cell infiltration and greater expression of immunosuppressive checkpoint regulators. Increased PD-L1 and LAG3 and reduced VISTA were observed in primary tumors compared to recurrent tumors. CONCLUSION: Immune cell infiltration and checkpoint regulator expression vary depending on functional status and presence of pituitary tumor initiating cells. Functional tumors may have a particularly immunosuppressive microenvironment. Further studies of immune checkpoint blockade of pituitary tumors, particularly functional tumors, are warranted, though combination therapy may be required.
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