title: Absence of class II-associated invariant chain peptide on leukemic blasts of patients promotes activation of autologous leukemia-reactive CD4+ T cells.
abstract: Immune escape in cancer poses a substantial obstacle to successful cancer immunotherapy. Multiple defects in HLA class I antigen presentation exist in cancer that may contribute to immune escape, but less is known about roles for HLA class II antigen presentation. On class II(+) leukemic blasts, the presence of class II-associated invariant chain peptide (CLIP) is known to be correlated with poor survival in acute myeloid leukemia (AML). In this study, we evaluated the functional significance of CLIP expression on leukemic blasts of AML patients. CD4(+) T cells from patients were cocultured with autologous CLIP(-) and CLIP(+) primary leukemic blasts and analyzed for several functional parameters by flow cytometry. Increased HLA-DR and IFN-γ expression was observed for CD4(+) T cells stimulated with CLIP(-) leukemic blasts, in contrast to CLIP(+) leukemic blasts, which indicated an activation and polarization of the CD4(+) T cells toward T-helper 1 cells. In addition, CLIP(-) leukemic blasts induced greater outgrowth of effector memory CD4(+) T cells (with HLA-DR-restricted T-cell receptor Vβ repertoires) that were associated with better leukemia-specific reactivity than with CLIP(+) leukemic blasts. Our findings offer a clinical rationale to downmodulate CLIP on leukemic blasts as a strategy to degrade immune escape and improve leukemia-specific T-cell immunity in AML patients.
authors.affiliation: Department of Hematology, Cancer Center Amsterdam and VU Institute for Cancer and Immunology, VU University Medical Center, The Netherlands. m.luijn@vumc.nl
authors.forename: Marvin M
authors.initials: MM
authors.lastname: van Luijn
authors.forename: Willemijn
authors.initials: W
authors.lastname: van den Ancker
authors.forename: Martine E D
authors.initials: ME
authors.lastname: Chamuleau
authors.forename: Adri
authors.initials: A
authors.lastname: Zevenbergen
authors.forename: Theresia M
authors.initials: TM
authors.lastname: Westers
authors.forename: Gert J
authors.initials: GJ
authors.lastname: Ossenkoppele
authors.forename: S Marieke
authors.initials: SM
authors.lastname: van Ham
authors.forename: Arjan A
authors.initials: AA
authors.lastname: van de Loosdrecht
mesh_terms: D000328:Adult; D000368:Aged; D000944:Antigens, Differentiation, B-Lymphocyte / Q000096:biosynthesis / Q000276:immunology*; D001752:Blast Crisis / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018920:Coculture Techniques; D005260:Female; D006684:HLA-DR Antigens / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D015470:Leukemia, Myeloid, Acute / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D014407:Tumor Cells, Cultured
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; D016693:Receptors, Antigen, T-Cell, alpha-beta; C045084:invariant chain