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1.
Cancer Discov ; 11(3): 696-713, 2021 03.
Article in English | MEDLINE | ID: mdl-33504579

ABSTRACT

Neoantigens are critical targets of antitumor T-cell responses. The ATLAS bioassay was developed to identify neoantigens empirically by expressing each unique patient-specific tumor mutation individually in Escherichia coli, pulsing autologous dendritic cells in an ordered array, and testing the patient's T cells for recognition in an overnight assay. Profiling of T cells from patients with lung cancer revealed both stimulatory and inhibitory responses to individual neoantigens. In the murine B16F10 melanoma model, therapeutic immunization with ATLAS-identified stimulatory neoantigens protected animals, whereas immunization with peptides associated with inhibitory ATLAS responses resulted in accelerated tumor growth and abolished efficacy of an otherwise protective vaccine. A planned interim analysis of a clinical study testing a poly-ICLC adjuvanted personalized vaccine containing ATLAS-identified stimulatory neoantigens showed that it is well tolerated. In an adjuvant setting, immunized patients generated both CD4+ and CD8+ T-cell responses, with immune responses to 99% of the vaccinated peptide antigens. SIGNIFICANCE: Predicting neoantigens in silico has progressed, but empirical testing shows that T-cell responses are more nuanced than straightforward MHC antigen recognition. The ATLAS bioassay screens tumor mutations to uncover preexisting, patient-relevant neoantigen T-cell responses and reveals a new class of putatively deleterious responses that could affect cancer immunotherapy design.This article is highlighted in the In This Issue feature, p. 521.


Subject(s)
Antigens, Neoplasm/immunology , Immunity, Cellular , Neoplasms/immunology , Neoplasms/pathology , T-Lymphocytes/immunology , Animals , Antigens, Neoplasm/genetics , Biomarkers, Tumor/genetics , Biomarkers, Tumor/immunology , Cancer Vaccines/administration & dosage , Cancer Vaccines/immunology , Cell Line, Tumor , Clinical Trials as Topic , DNA Mutational Analysis , Disease Models, Animal , Disease Progression , Genomics/methods , Humans , Immunogenicity, Vaccine , Melanoma, Experimental , Mice , Mutation , Neoplasms/genetics , Neoplasms/therapy , T-Lymphocytes/metabolism , T-Lymphocytes/pathology , Treatment Outcome , Vaccination
2.
J Immunol ; 202(4): 1112-1123, 2019 02 15.
Article in English | MEDLINE | ID: mdl-30635395

ABSTRACT

CD4 Th cells are organizers of the immune response, directing other immune cells to initiate and maintain effective humoral and cellular immunity. CD4 T cells differentiate into distinct Th effector or regulatory subsets in response to signals delivered to them during the course of infection. Ikaros is a transcription factor that is expressed in blood cells from the level of the hematopoietic stem cell. It is required for normal thymic T cell development and serves as a tumor suppressor, as lack of Ikaros in developing lymphoid cells results in leukemia. To study the role of Ikaros in CD4 T cell differentiation and function, an Ikaros conditional knockout mouse was developed such that Ikaros expression was deleted specifically in mature T cells, thus avoiding defects observed in germline Ikaros mutant mice. Using this model system, we have shown that in the absence of Ikaros, CD4 T cells are able to attain Th1, Th2, and Th17, but not inducible regulatory T, cell fates. However, they show enhanced expression of a cohort of proinflammatory cytokines, resulting in differentiation of Th17 cells with a phenotype that has been associated with autoimmunity and pathological inflammation. In addition, we define Ikaros as a repressor of the gene program associated with the response to type I IFNs, another key pathway whose deregulation is linked to autoimmunity. Taken together, these data definitively define Ikaros as a critical regulator at the center of the inflammatory response in T cells and highlight a potential role in suppressing autoimmunity.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Ikaros Transcription Factor/immunology , Inflammation/immunology , Animals , Female , Ikaros Transcription Factor/deficiency , Ikaros Transcription Factor/genetics , Inflammation/genetics , Interferon Type I/immunology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mutation
3.
Immunology ; 152(3): 494-506, 2017 11.
Article in English | MEDLINE | ID: mdl-28670688

ABSTRACT

Ikaros is a transcription factor that regulates lymphocyte development from the level of the haematopoietic stem cell. Lack of Ikaros reduces the ability of progenitor cells to commit to the T-cell lineage, resulting in reduced numbers of early thymic T-cell progenitors and mature T cells. Mature CD4 T cells that lack Ikaros have defects in proliferation, T helper cell differentiation, cytokine expression and the ability to become anergic. A role for Ikaros in the naive T cell has not yet been identified. The receptors interleukin-7 receptor α (IL-7Rα) and l-selectin are important for ensuring survival and proper homing of naive T cells, respectively. Here we show that lack of Ikaros leads to reduced expression of these receptors in naive T cells, which impacts their ability to home and survive in response to IL-7. We define the mechanism underlying this phenotype as a requirement for Ikaros in maintenance of expression of Foxo1, a transcriptional regulator that is required for their expression. We also demonstrate that CD4 T cells lacking Ikaros are significantly crippled in their ability to become induced regulatory T cells, a phenotype also linked to reduced Foxo1 expression. Finally, we show that restoring Ikaros function to Ikaros-deficient CD4 T cells increases levels of Foxo1 message. Together, these studies define, for the first time, a role for Ikaros in naive T cells and establish it as the first transcriptional regulator required for maintaining levels of Foxo1 gene expression in these cells.


Subject(s)
CD4-Positive T-Lymphocytes/metabolism , Forkhead Box Protein O1/metabolism , Ikaros Transcription Factor/deficiency , Adoptive Transfer , Animals , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/transplantation , Cell Differentiation , Cell Survival , Cells, Cultured , Chemotaxis, Leukocyte , Forkhead Box Protein O1/genetics , Forkhead Box Protein O1/immunology , Gene Expression Regulation , Genotype , Ikaros Transcription Factor/genetics , Ikaros Transcription Factor/immunology , Interleukin-7/pharmacology , L-Selectin/genetics , L-Selectin/immunology , L-Selectin/metabolism , Mice, 129 Strain , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Phenotype , Receptors, Interleukin-17/genetics , Receptors, Interleukin-17/immunology , Receptors, Interleukin-17/metabolism , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Time Factors , Transcription, Genetic , Transfection
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