Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses.
T cells infiltrating tumors have a decreased expression of signal transduction proteins, a diminished ability to proliferate, and a decreased production of cytokines. The mechanisms causing these changes have remained unclear. We demonstrated recently that peritoneal macrophages stimulated with interleukin 4 + interleukin 13 produce arginase I, which decreases the expression of the T-cell receptor CD3zeta chain and impairs T-cell responses. Using a 3LL murine lung carcinoma model we tested whether arginase I was produced in the tumor microenvironment and could decrease CD3zeta expression and impair T-cell function. The results show that a subpopulation of mature tumor-associated myeloid cells express high levels of arginase I, whereas tumor cells and infiltrating lymphocytes do not. Arginase I expression in the tumor was seen on day 7 after tumor injection. Tumor-associated myeloid cells also expressed high levels of cationic amino acid transporter 2B, which allowed them to rapidly incorporate L-Arginine (L-Arg) and deplete extracellular L-Arg in vitro. L-Arg depletion by tumor-associated myeloid cells blocked the re-expression of CD3zeta in stimulated T cells and inhibited antigen-specific proliferation of OT-1 and OT-2 cells. The injection of the arginase inhibitor N-hydroxy-nor-L-Arg blocked growth of s.c. 3LL lung carcinoma in mice. High levels of arginase I were also found in tumor samples of patients with non-small cell carcinoma. Therefore, arginase I production by mature myeloid cells in the tumor microenvironment may be a central mechanism for tumor evasion and may represent a target for new therapies.
Tumor Immunology Program, Stanley S. Scott Cancer Center, Louisiana State University, Health Sciences Center, New Orleans, Louisiana 70112, USA.
Paulo C
PC
Rodriguez
David G
DG
Quiceno
Jovanny
J
Zabaleta
Blair
B
Ortiz
Arnold H
AH
Zea
Maria B
MB
Piazuelo
Alberto
A
Delgado
Pelayo
P
Correa
Jason
J
Brayer
Eduardo M
EM
Sotomayor
Scott
S
Antonia
Juan B
JB
Ochoa
Augusto C
AC
Ochoa
D000595:Amino Acid Sequence; D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000276:immunology*; D017252:CD3 Complex / Q000096:biosynthesis / Q000276:immunology; D018827:Carcinoma, Lewis Lung / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D002455:Cell Division / Q000502:physiology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008969:Molecular Sequence Data; D022423:Myeloid Cells / Q000201:enzymology / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D018984:Epitopes, T-Lymphocyte; D011948:Receptors, Antigen, T-Cell; D001119:Arginase