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.
Rotondo
Rita
R
Department of Translational Oncology, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
Barisione
Gaia
G
Mastracci
Luca
L
Grossi
Francesco
F
Orengo
Anna Maria
AM
Costa
Roberta
R
Truini
Mauro
M
Fabbi
Marina
M
Ferrini
Silvano
S
Barbieri
Ottavia
O
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