title: Modulation of T-cell activation by malignant melanoma initiating cells.
abstract: Highly immunogenic cancers such as malignant melanoma are capable of inexorable tumor growth despite the presence of antitumor immunity. Thus, only a restricted minority of tumorigenic malignant cells may possess the phenotypic and functional characteristics needed to modulate tumor-directed immune activation. Here we provide evidence supporting this hypothesis. Tumorigenic ABCB5(+) malignant melanoma initiating cells (MMICs) possessed the capacity to preferentially inhibit IL-2-dependent T-cell activation and to support, in a B7.2-dependent manner, induction of CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs). Compared with melanoma bulk cell populations, ABCB5(+) MMICs displayed lower levels of MHC class I, aberrant positivity for MHC class II, and lower expression levels of the melanoma-associated antigens MART-1, ML-IAP, NY-ESO-1, and MAGE-A. Additionally, these tumorigenic ABCB5(+) subpopulations preferentially expressed the costimulatory molecules B7.2 and PD-1, both in established melanoma xenografts and in clinical tumor specimens. In immune activation assays, MMICs inhibited mitogen-dependent human peripheral blood mononuclear cell (PBMC) proliferation and IL-2 production more efficiently than ABCB5(-) melanoma cell populations. Moreover, coculture with ABCB5(+) MMICs increased the abundance of Tregs, in a B7.2 signaling-dependent manner, along with IL-10 production by mitogen-activated PBMCs. Consistent with these findings, MMICs also preferentially inhibited IL-2 production and induced IL-10 secretion by cocultured patient-derived, syngeneic PBMCs. Our findings identify novel T-cell modulatory functions of ABCB5(+) melanoma subpopulations and suggest specific roles for these MMICs in the evasion of antitumor immunity and in cancer immunotherapeutic resistance.
authors.affiliation: Transplantation Research Center, Children's Hospital Boston, Boston, Massachusetts 02115, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schatton
authors.forename: Ute
authors.initials: U
authors.lastname: Schütte
authors.forename: Natasha Y
authors.initials: NY
authors.lastname: Frank
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhan
authors.forename: André
authors.initials: A
authors.lastname: Hoerning
authors.forename: Susanne C
authors.initials: SC
authors.lastname: Robles
authors.forename: Jun
authors.initials: J
authors.lastname: Zhou
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
authors.forename: Giulio C
authors.initials: GC
authors.lastname: Spagnoli
authors.forename: George F
authors.initials: GF
authors.lastname: Murphy
authors.forename: Markus H
authors.initials: MH
authors.lastname: Frank
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000276:immunology; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008213:Lymphocyte Activation; D008545:Melanoma / Q000276:immunology* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: C480744:ABCB5 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000951:Antigens, Neoplasm