title: Prospective analysis of antigen-specific immunity, stem-cell antigens, and immune checkpoints in monoclonal gammopathy.
abstract: Blockade of immune checkpoints (ICPs) has led to impressive responses in cancer patients. However, the impact of preexisting immunity and ICPs on the risk of malignant transformation in human preneoplasia has not been prospectively studied. We prospectively analyzed antigen-specific B/T-cell immunity, immune composition of the tumor microenvironment, and the expression of a panel of ICPs on tumor and tumor-infiltrating immune cells in 305 patients with asymptomatic monoclonal gammopathy enrolled in S0120 under the auspices of SWOG. T-cell immunity against stem-cell antigen SOX2 and preserved humoral responses at study entry independently correlated with reduced risk of progression to clinical myeloma. Among the ICPs analyzed, expression of programmed death-ligand 1 (PD-L1) on tumor and infiltrating T cells correlated with increased risk of clinical malignancy, and blockade of this pathway boosted anti-SOX2 immunity in culture. These data suggest that stem-cell antigens and PD-L1 may be targeted for immunoprevention of myeloma. This trial was registered at www.clinicaltrials.gov as #NCT00900263.
authors.affiliation: Yale University, New Haven, CT;
authors.forename: Madhav V
authors.initials: MV
authors.lastname: Dhodapkar
authors.affiliation: SWOG Statistical Center, Seattle, WA; Cancer Research and Biostatistics, Seattle, WA;
authors.forename: Rachael
authors.initials: R
authors.lastname: Sexton
authors.affiliation: Yale University, New Haven, CT;
authors.forename: Rituparna
authors.initials: R
authors.lastname: Das
authors.affiliation: Yale University, New Haven, CT;
authors.forename: Kavita M
authors.initials: KM
authors.lastname: Dhodapkar
authors.affiliation: Yale University, New Haven, CT;
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Yale University, New Haven, CT;
authors.forename: Ranjini
authors.initials: R
authors.lastname: Sundaram
authors.affiliation: Yale University, New Haven, CT;
authors.forename: Sonal
authors.initials: S
authors.lastname: Soni
authors.affiliation: SWOG Statistical Center, Seattle, WA; Cancer Research and Biostatistics, Seattle, WA;
authors.forename: John J
authors.initials: JJ
authors.lastname: Crowley
authors.affiliation: MD Anderson Cancer Center, Houston, TX; and.
authors.forename: Robert Z
authors.initials: RZ
authors.lastname: Orlowski
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR.
authors.forename: Bart
authors.initials: B
authors.lastname: Barlogie
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D060890:B7-H1 Antigen / Q000276:immunology; D005260:Female; D006801:Humans; D007111:Immunity, Cellular; D008297:Male; D009101:Multiple Myeloma / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D011446:Prospective Studies; D055748:SOXB1 Transcription Factors / Q000276:immunology*; D013234:Stem Cells / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
chemical_list: D000951:Antigens, Neoplasm; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors