IL-8 induces exocytosis of arginase 1 by neutrophil polymorphonuclears in nonsmall cell lung cancer.
Arginase 1 (ARG1) inhibits T-cell proliferation by degrading extracellular arginine, which results in decreased responsiveness of T cells to CD3/TCR stimulation. In humans, ARG1 is stored in inactive form within granules of polymorphonuclear neutrophils (PMNs) and gets activated on release. We studied the role of PMNs-related ARG1 activity in nonsmall cell lung cancer (NSLC), in which tumor-infiltrating lymphocytes showed reduced proliferation in response to CD3/TCR triggering. Patients with NSCLC had increased ARG1 plasma levels as compared to healthy controls. Furthermore, immunohistochemistry showed that tumor-infiltrating PMNs display reduced intracellular ARG1, in comparison to intravascular or peritumoral PMNs, suggesting a role of tumor microenvironment in ARG1 release. Indeed, supernatants of NSCLC cell lines induced exocytosis of ARG1 from PMNs. All (4/4) NSCLC cell lines and all (7/7) CD14- cell samples from NSCLC expressed interleukin (IL)-8 mRNA, whereas TNFalpha mRNA was expressed by 1 cell line and by 2 tumor specimens. Furthermore, all NSCLC cell lines secreted immunoreactive IL-8, albeit at different levels. IL-8 was as effective as TNFalpha in triggering ARG1 release and the 2 cytokines acted synergistically. Secreted ARG1 was biologically active and catabolized extracellular arginine. The supernatant of IL-8 gene-silenced NSCLC cells did not mediate ARG1 release by PMNs. Altogether these findings demonstrate a role of IL-8 in ARG1 exocytosis by PMNs and indicate that, due at least in part to IL-8 secreted by NSCLC cells, PMNs infiltrating NSCLC release ARG1. This phenomenon could contribute to local immune suppression.
Department of Translational Oncology, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Rita
R
Rotondo
Gaia
G
Barisione
Luca
L
Mastracci
Francesco
F
Grossi
Anna Maria
AM
Orengo
Roberta
R
Costa
Mauro
M
Truini
Marina
M
Fabbi
Silvano
S
Ferrini
Ottavia
O
Barbieri
D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology; D000368:Aged; D001119:Arginase / Q000097:blood*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000473:pathology; D016022:Case-Control Studies; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D005089:Exocytosis; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D016209:Interleukin-8 / Q000494:pharmacology*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000201:enzymology* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
C508606:CXCL8 protein, human; D016209:Interleukin-8; D012333:RNA, Messenger; D001119:Arginase