Expression of the apoptosis inhibitor protease inhibitor 9 predicts clinical outcome in vaccinated patients with stage III and IV melanoma.
OBJECTIVE
There have been reports of successful treatment of metastatic melanoma patients with active specific immunotherapy (ASI) using irradiated autologous tumor cell vaccination. It is still unknown why some patients respond and others do not. Tumor cells can evade the immune system, for example through interference with antigen presentation by down-regulation of MHC molecules or expressing proteins interfering with cytotoxic lymphocyte-induced apoptosis like the granzyme B antagonist protease inhibitor 9 (PI-9).


METHODS
PI-9 expression was detected in melanoma cell lines. To investigated if PI-9 is important in the response to ASI, paraffin-embedded tissues from stage III or IV melanoma patients were stained.


RESULTS
PI-9 is expressed in melanoma cells and expression in metastasized melanoma cells is, in this group of patients, an adverse prognostic marker with regard to overall and disease-free survival. Moreover, loss of MHC-1 expression frequently occurs during tumor progression but is not associated with poor clinical outcome. Interestingly, melanoma patients with a favorable clinical outcome after ASI therapy usually have high percentages of activated (granzyme B-positive) tumor-infiltrating lymphocytes at time of first diagnosis and low percentages of activated lymphocytes at time of recurrent tumor.


CONCLUSIONS
Expression of PI-9 in metastatic melanoma cells is associated with unfavorable clinical outcome whereas MHC-1 down-regulation is not. Although it cannot be proven that PI-9 expression is directly responsible for failure of immunotherapy, these data suggest that expression of PI-9 could be an important immune escape mechanism and that modulation of this inhibitor may enhance the efficacy of immunotherapy.
van Houdt
Inge S
IS
Department of Pathology, VU Medical Center, Amsterdam, Netherlands.
Oudejans
Joost J
JJ
van den Eertwegh
Alfonsus J M
AJ
Baars
Arnold
A
Vos
Wim
W
Bladergroen
Bellinda A
BA
Rimoldi
Donata
D
Muris
Jettie J F
JJ
Hooijberg
Erik
E
Gundy
Chad M
CM
Meijer
Chris J L M
CJ
Kummer
Jean A
JA
D000328:Adult; D000368:Aged; D017209:Apoptosis; D015153:Blotting, Western; D019496:Cancer Vaccines / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D005805:Genes, MHC Class I / Q000502:physiology; D053804:Granzymes; D006801:Humans; D007124:Immunoenzyme Techniques; D007167:Immunotherapy; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology*; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000556:secondary / Q000628:therapy; D008875:Middle Aged; D009367:Neoplasm Staging; D012697:Serine Endopeptidases / Q000737:chemistry; D015843:Serpins / Q000378:metabolism*; D012878:Skin Neoplasms / Q000276:immunology* / Q000556:secondary / Q000628:therapy; D015996:Survival Rate; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D019496:Cancer Vaccines; C102316:SERPINB9 protein, human; D015843:Serpins; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases