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24/Vβ11 Invariant NKT Cells in Intrahepatic Malignant Tumors 1
* Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Lausanne Branch,
Institut Universitaire de Pathologie and
Department of Surgery, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland;
Ludwig Institute for Cancer Research, Lausanne Branch and
¶ Swiss Institute for Experimental Cancer Research, University of Lausanne, Epalinges, Switzerland; and
|| Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx NY 10461
Invariant NKT cells (iNKT cells) recognize glycolipid Ags via an invariant TCR 
-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 V24/Vβ11 iNKT cells were increased in tumors, especially in patients with hepatocellular carcinoma. The proportions of CD4+, double negative, and CD8+ 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.
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1 This work was supported by Swiss National Science Foundation (FNRS) Grant 32-64055.00 and the Emma Muschamp Foundation and was part of the Ph.D. thesis of G.B. at the University of Lausanne. V.C. is supported by FNRS Grant 320000-112581 and P.M.A. was supported by the FNRS National Center of Competence in Research Program in Molecular Oncology.
2 Address correspondence and reprint requests to Dr. Daniel E. Speiser, Ludwig Institute for Cancer Research, Division of Clinical Onco-Immunology, Hôpital Orthopédique, Niveau 5, Aile Est, CH-1011 Lausanne, Switzerland. E-mail address: daniel.speiser{at}hospvd.ch
3 Abbreviations used in this paper: iNKT, invariant NKT cell; DAPI, 4',4'-diamidino-2-phenylindole; DC, dendritic cell; DN, double negative (CD4/CD8); -GalCer, -galactosylceramide; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HD, healthy donor; IHL, intrahepatic lymphocyte; PBC, primary biliary cirrhosis; SP, single positive; TIL, tumor-infiltrating lymphocyte.
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