title: Enrichment of human CD4+ V(alpha)24/Vbeta11 invariant NKT cells in intrahepatic malignant tumors.
abstract: Invariant NKT cells (iNKT cells) recognize glycolipid Ags via an invariant TCR alpha-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 Valpha24/Vbeta11 iNKT cells were increased in tumors, especially in patients with hepatocellular carcinoma. The proportions of CD4(+), double negative, and CD8alpha(+) 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.
authors.affiliation: Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Bricard
authors.forename: Valerie
authors.initials: V
authors.lastname: Cesson
authors.forename: Estelle
authors.initials: E
authors.lastname: Devevre
authors.forename: Hanifa
authors.initials: H
authors.lastname: Bouzourene
authors.forename: Catherine
authors.initials: C
authors.lastname: Barbey
authors.forename: Nathalie
authors.initials: N
authors.lastname: Rufer
authors.forename: Jin S
authors.initials: JS
authors.lastname: Im
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Alves
authors.forename: Olivier
authors.initials: O
authors.lastname: Martinet
authors.forename: Nermin
authors.initials: N
authors.lastname: Halkic
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Cerottini
authors.forename: Pedro
authors.initials: P
authors.lastname: Romero
authors.forename: Steven A
authors.initials: SA
authors.lastname: Porcelli
authors.forename: H Robson
authors.initials: HR
authors.lastname: Macdonald
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Speiser