Expression of the granzyme B inhibitor, protease inhibitor 9, by tumor cells in patients with non-Hodgkin and Hodgkin lymphoma: a novel protective mechanism for tumor cells to circumvent the immune system?

• Published in: Blood 2002-01, Vol.99 (1), p.232-237
• Main Authors: Bladergroen, Bellinda A., Meijer, Chris J.L.M., ten Berge, Rosita L., Hack, C. Erik, Muris, Jettie J.F., Dukers, Danny F., Chott, Andreas, Kazama, Yoshiaki, Oudejans, Joost J., van Berkum, Oskar, Kummer, J. Alain
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal; Apoptosis; Biological and medical sciences; Granzymes; Hematologic and hematopoietic diseases; Histocytochemistry; Hodgkin Disease - immunology; Hodgkin Disease - metabolism; Humans; Immunohistochemistry; Killer Cells, Natural - immunology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma, B-Cell - immunology; Lymphoma, B-Cell - metabolism; Lymphoma, Non-Hodgkin - immunology; Lymphoma, Non-Hodgkin - metabolism; Lymphoma, T-Cell - immunology; Lymphoma, T-Cell - metabolism; Medical sciences; Serine Endopeptidases - metabolism; Serpins - analysis; T-Lymphocytes, Cytotoxic - enzymology; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - pathology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V99.1.232

In tumor cells, the serine protease granzyme B is the primary mediator of apoptosis induced by cytotoxic T lymphocytes (CTLs)/natural killer (NK) cells. The human intracellular serpin proteinase inhibitor 9 (PI9) is the only known human protein able to inhibit the proteolytic activity of granzyme B. When present in the cytoplasm of T lymphocytes, PI9 is thought to protect CTLs against apoptosis induced by their own misdirected granzyme B. Based on the speculation that tumors may also express PI9 to escape CTL/NK cell surveillance, immunohistochemical studies on the expression of PI9 in various lymphomas were performed. Ninety-two cases of T-cell non-Hodgkin lymphoma (NHL), 75 cases of B-cell NHL, and 57 cases of Hodgkin lymphomas were stained with a PI9-specific monoclonal antibody. In T-cell NHL, highest PI9 expression was found in the extranodal T-cell NHL. In nearly 90% of enteropathy-type T-cell NHLs and 80% of NK/T-cell, nasal-type lymphomas, the majority of the tumor cells expressed PI9. In nodal T-anaplastic large cell lymphomas and peripheral T-cell lymphomas (not otherwise specified), PI9 expression occurred less frequently. In B-cell NHL, PI9 expression was associated with high-grade malignancy; 43% of diffuse large B-cell lymphomas showed PI9+ tumor cells. Finally, PI9 expression was also found in 10% of Hodgkin lymphomas. This is the first report describing the expression of the granzyme B inhibitor PI9 in human neoplastic cells in vivo. Expression of this inhibitor is yet another mechanism used by tumor cells to escape their elimination by cytotoxic lymphocytes.