title: The Hypothesis of the Human iNKT/Innate CD8(+) T-Cell Axis Applied to Cancer: Evidence for a Deficiency in Chronic Myeloid Leukemia.
abstract: We recently identified a new human subset of NK-like [KIR/NKG2A(+)] CD8(+) T cells with a marked/memory phenotype, high Eomesodermin expression, potent antigen-independent cytotoxic activity, and the capacity to generate IFN-γ rapidly after exposure to pro-inflammatory cytokines. These features support the hypothesis that this new member of the innate T cell family in humans, hereafter referred to as innate CD8(+) T cells, has a role in cancer immune surveillance analogous to invariant natural killer T (iNKT) cells. Here, we report the first quantitative and functional analysis of innate CD8(+) T cells in a physiopathological context in humans, namely chronic myeloid leukemia (CML), a well-characterized myeloproliferative disorder. We have chosen CML based on our previous report that IL-4 production by iNKT cells was deficient in CML patients at diagnosis and considering the recent evidence in mice that IL-4 promotes the generation/differentiation of innate CD8(+) T cells. We found that the pool of innate CD8(+) T cells was severely reduced in the blood of CML patients at diagnosis. Moreover, like iNKT and NK cells, innate CD8(+) T cells were functionally impaired, as attested by their loss of antigen-independent cytotoxic activity and IFN-γ production in response to innate-like stimulation with IL-12 + IL-18. Remarkably, as previously reported for IL-4 production by iNKT cells, both quantitative and functional deficiencies of innate CD8(+) T cells were at least partially corrected in patients having achieved complete cytogenetic remission following tyrosine kinase inhibitor therapy. Finally, direct correlation between the functional potential of innate CD8(+) T and iNKT cells was found when considering all healthy donors and CML patients in diagnosis and remission, in accordance with the iNKT cell-dependent generation of innate CD8(+) T cells reported in mice. All in all, our data demonstrate that CML is associated with deficiencies of innate CD8(+) T cells that are restored upon remission, thereby suggesting their possible contribution to disease control. More generally, our study strongly supports the existence of an innate iNKT/innate CD8(+) T-cell axis in humans and reveals its potential contribution to the restoration of tumor immune surveillance.
authors.affiliation: INSERM 1082, Poitiers, France; Service d'Immunologie et Inflammation, Poitiers, France; CHU de Poitiers, Poitiers, France; Université de Poitiers, Poitiers, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Jacomet
authors.affiliation: INSERM 1082, Poitiers, France; CHU de Poitiers, Poitiers, France; Université de Poitiers, Poitiers, France; Service d'Hématologie et d'Oncologie Biologique, Poitiers, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Cayssials
authors.affiliation: INSERM 1082, Poitiers, France; CHU de Poitiers, Poitiers, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Barbarin
authors.affiliation: INSERM 1082, Poitiers, France; CHU de Poitiers, Poitiers, France; Service d'Hématologie et d'Oncologie Biologique, Poitiers, France.
authors.forename: Deborah
authors.initials: D
authors.lastname: Desmier
authors.affiliation: INSERM 1082, Poitiers, France; Université de Poitiers, Poitiers, France.
authors.forename: Sara
authors.initials: S
authors.lastname: Basbous
authors.affiliation: INSERM 1082, Poitiers, France; Université de Poitiers, Poitiers, France.
authors.forename: Lucie
authors.initials: L
authors.lastname: Lefèvre
authors.affiliation: INSERM 1082 , Poitiers , France.
authors.forename: Anaïs
authors.initials: A
authors.lastname: Levescot
authors.affiliation: INSERM 1082, Poitiers, France; CHU de Poitiers, Poitiers, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Robin
authors.affiliation: INSERM 1082, Poitiers, France; CHU de Poitiers, Poitiers, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Piccirilli
authors.affiliation: INSERM 1082, Poitiers, France; CHU de Poitiers, Poitiers, France; Etablissement Français du Sang Centre-Atlantique, Site de Poitiers, Poitiers, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Giraud
authors.affiliation: CHU de Poitiers, Poitiers, France; Université de Poitiers, Poitiers, France; INSERM CIC-1402, Poitiers, France.
authors.forename: François
authors.initials: F
authors.lastname: Guilhot
authors.affiliation: INSERM CIC-1402, Poitiers, France; Service d'Hématologie Clinique, Hôpital Henri Mondor, Créteil, France; Université Paris-Est, Créteil, France.
authors.forename: Lydia
authors.initials: L
authors.lastname: Roy
authors.affiliation: INSERM 1082, Poitiers, France; CHU de Poitiers, Poitiers, France; Université de Poitiers, Poitiers, France.
authors.forename: André
authors.initials: A
authors.lastname: Herbelin
authors.affiliation: INSERM 1082, Poitiers, France; Service d'Immunologie et Inflammation, Poitiers, France; CHU de Poitiers, Poitiers, France; Université de Poitiers, Poitiers, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Gombert
keywords: NK-like CD8(+) T cells; chronic myeloid leukemia; iNKT cells; innate CD8(+) T cells; tyrosine kinase inhibitor