Arginase 2 is expressed by human lung cancer, but it neither induces immune suppression, nor affects disease progression.
In human prostate cancer, Arginase 2 (ARG2) and nitric oxide synthase (NOS) are concomitantly expressed by tumor cells, and induce tumor immune escape via peroxynitrite-dependent Tyrosine nitrosylation. Since there were no data regarding this immune suppressive mechanism in other tumor types, and an evaluation of its clinical relevance in human tumors had still to be provided, we have investigated presence and clinical relevance of ARG2 and NOS expression in lung cancer. No evidence of NOS expression was found, no significant NOS enzymatic activity was detected. Instead, ARG2 protein was expressed by tumor cells. In a cohort of 120 patients, the amount of ARG2-positive tumor cells was significantly higher in small cell lung cancers (SCLC) than in non-small cell lung cancers (NSCLC). Large cell undifferentiated carcinomas had twice ARG2 than the other NSCLC subtypes. ARG2 expression was increased in Grade 3 tumors, as compared to Grades 1 and 2. However, no relationship was found with tumor size and stage, and with patient survival. Indeed, the enzyme was active, since the Arginine catabolite Ornithine was produced, but Arginine depletion was not attained. In addition, nitrotyrosine was not found in tumor tissue. Accordingly, when tumor cells isolated from lung cancer were incubated with activated autologous T cells, no inhibition of proliferation was detected. Our results indicate that ARG2 is expressed in lung cancer, but it does not induce tumor immune escape and does not affect disease progression, most probably due to the lack of concomitant NOS expression.
Department of Translational Oncology, National Institute for Cancer Research, Genoa, Italy.
Rita
R
Rotondo
Luca
L
Mastracci
Tiziana
T
Piazza
Gaia
G
Barisione
Marina
M
Fabbi
Michela
M
Cassanello
Roberta
R
Costa
Barbara
B
Morandi
Simonetta
S
Astigiano
Alfredo
A
Cesario
Maria P
MP
Sormani
Guido
G
Ferlazzo
Francesco
F
Grossi
Giovanni B
GB
Ratto
Silvano
S
Ferrini
Guido
G
Frumento
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001119:Arginase / Q000378:metabolism*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000276:immunology; D018288:Carcinoma, Small Cell / Q000201:enzymology / Q000276:immunology; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007558:Italy; D008175:Lung Neoplasms / Q000201:enzymology* / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D009367:Neoplasm Staging; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D030421:Peroxynitrous Acid / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes; D014443:Tyrosine / Q000031:analogs & derivatives / Q000096:biosynthesis
D009573:Nitrites; D030421:Peroxynitrous Acid; C002744:3-nitrotyrosine; D014443:Tyrosine; D019001:Nitric Oxide Synthase; C477631:ARG2 protein, human; D001119:Arginase