TY - JOUR
T1 - Enrichment of human CD4+ Vα24/Vβ11 invariant NKT cells in intrahepatic malignant tumors
AU - Bricard, Gabriel
AU - Cesson, Valerie
AU - Devevre, Estelle
AU - Bouzourene, Hanifa
AU - Barbey, Catherine
AU - Rufer, Nathalie
AU - Im, Jin S.
AU - Alves, Pedro M.
AU - Martinet, Olivier
AU - Halkic, Nermin
AU - Cerottini, Jean Charles
AU - Romero, Pedro
AU - Porcelli, Steven A.
AU - MacDonald, H. Robson
AU - Speiser, Daniel E.
PY - 2009/4/15
Y1 - 2009/4/15
N2 - Invariant NKT cells (iNKT cells) recognize glycolipid Ags via an invariant TCR α-chain and play a central role in various immune responses. Although human CD4+ and CD4- iNKT cell subsets both produce Th1 cytokines, the CD4+ subset displays an enhanced ability to secrete Th2 cytokines and shows regulatory activity. We performed an ex vivo analysis of blood, liver, and tumor iNKT cells from patients with hepatocellular carcinoma and metastases from uveal melanoma or colon carcinoma. Frequencies of Vα24/Vβ11 iNKT cells were increased in tumors, especially in patients with hepatocellular carcinoma. The proportions of CD4+, double negative, and CD8α+ iNKT cell subsets in the blood of patients were similar to those of healthy donors. However, we consistently found that the proportion of CD4+ iNKT cells increased gradually from blood to liver to tumor. Furthermore, CD4+ iNKT cell clones generated from healthy donors were functionally distinct from their CD4- counterparts, exhibiting higher Th2 cytokine production and lower cytolytic activity. Thus, in the tumor microenvironment the iNKT cell repertoire is modified by the enrichment of CD4+ iNKT cells, a subset able to generate Th2 cytokines that can inhibit the expansion of tumor Ag-specific CD8+ T cells. Because CD4+ iNKT cells appear inefficient in tumor defense and may even favor tumor growth and recurrence, novel iNKT-targeted therapies should restore CD4- iNKT cells at the tumor site and specifically induce Th1 cytokine production from all iNKT cell subsets.
AB - Invariant NKT cells (iNKT cells) recognize glycolipid Ags via an invariant TCR α-chain and play a central role in various immune responses. Although human CD4+ and CD4- iNKT cell subsets both produce Th1 cytokines, the CD4+ subset displays an enhanced ability to secrete Th2 cytokines and shows regulatory activity. We performed an ex vivo analysis of blood, liver, and tumor iNKT cells from patients with hepatocellular carcinoma and metastases from uveal melanoma or colon carcinoma. Frequencies of Vα24/Vβ11 iNKT cells were increased in tumors, especially in patients with hepatocellular carcinoma. The proportions of CD4+, double negative, and CD8α+ iNKT cell subsets in the blood of patients were similar to those of healthy donors. However, we consistently found that the proportion of CD4+ iNKT cells increased gradually from blood to liver to tumor. Furthermore, CD4+ iNKT cell clones generated from healthy donors were functionally distinct from their CD4- counterparts, exhibiting higher Th2 cytokine production and lower cytolytic activity. Thus, in the tumor microenvironment the iNKT cell repertoire is modified by the enrichment of CD4+ iNKT cells, a subset able to generate Th2 cytokines that can inhibit the expansion of tumor Ag-specific CD8+ T cells. Because CD4+ iNKT cells appear inefficient in tumor defense and may even favor tumor growth and recurrence, novel iNKT-targeted therapies should restore CD4- iNKT cells at the tumor site and specifically induce Th1 cytokine production from all iNKT cell subsets.
UR - http://www.scopus.com/inward/record.url?scp=65249176389&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=65249176389&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.0711086
DO - 10.4049/jimmunol.0711086
M3 - Article
C2 - 19342695
AN - SCOPUS:65249176389
SN - 0022-1767
VL - 182
SP - 5140
EP - 5151
JO - Journal of Immunology
JF - Journal of Immunology
IS - 8
ER -