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?
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.
Bladergroen
Bellinda A
BA
Department of Pathology, Free University Medical Center, Amsterdam, The Netherlands.
Meijer
Chris J L M
CJ
ten Berge
Rosita L
RL
Hack
C Erik
CE
Muris
Jettie J F
JJ
Dukers
Danny F
DF
Chott
Andreas
A
Kazama
Yoshiaki
Y
Oudejans
Joost J
JJ
van Berkum
Oskar
O
Kummer
J Alain
JA
D000911:Antibodies, Monoclonal; D017209:Apoptosis; D053804:Granzymes; D006651:Histocytochemistry; D006689:Hodgkin Disease / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007694:Killer Cells, Natural / Q000276:immunology; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000378:metabolism; D008228:Lymphoma, Non-Hodgkin / Q000276:immunology* / Q000378:metabolism*; D016399:Lymphoma, T-Cell / Q000276:immunology / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*; D015843:Serpins / Q000032:analysis*; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology / Q000276:immunology / Q000473:pathology
D000911:Antibodies, Monoclonal; C102316:SERPINB9 protein, human; D015843:Serpins; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases