title: Reversal of NK-cell exhaustion in advanced melanoma by Tim-3 blockade.
abstract: The immunoregulatory protein T-cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) mediates T-cell exhaustion and contributes to the suppression of immune responses in both viral infections and tumors. Tim-3 blockade reverses the exhausted phenotype of CD4+ and CD8+ T cells in several chronic diseases, including melanoma. Interestingly, natural killer (NK) cells constitutively express Tim-3; however, the role of Tim-3 in modulating the function of these innate effector cells remains unclear, particularly in human diseases. In this study, we compared the function of Tim-3 in NK cells from healthy donors and patients with metastatic melanoma. NK cells from the latter were functionally impaired/exhausted, and Tim-3 blockade reversed this exhausted phenotype. Moreover, Tim-3 expression levels were correlated with the stage of the disease and poor prognostic factors. These data indicate that Tim-3 can function as an NK-cell exhaustion marker in advanced melanoma and support the development of Tim-3-targeted therapies to restore antitumor immunity.
authors.affiliation: Authors' Affiliations: Programme for Advanced Medical Education, Lisbon, Portugal.
authors.forename: Ines Pires
authors.initials: IP
authors.lastname: da Silva
authors.forename: Anne
authors.initials: A
authors.lastname: Gallois
authors.forename: Sonia
authors.initials: S
authors.lastname: Jimenez-Baranda
authors.forename: Shaukat
authors.initials: S
authors.lastname: Khan
authors.forename: Ana C
authors.initials: AC
authors.lastname: Anderson
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
authors.forename: Iman
authors.initials: I
authors.lastname: Osman
authors.forename: Nina
authors.initials: N
authors.lastname: Bhardwaj
mesh_terms: D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D045744:Cell Line, Tumor; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D009367:Neoplasm Staging; D010641:Phenotype; D011379:Prognosis; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins; D015375:Receptors, Interleukin-2