title: T cells in chronic lymphocytic leukemia display dysregulated expression of immune checkpoints and activation markers.
abstract: Chronic lymphocytic leukemia is characterized by impaired immune functions largely due to profound T-cell defects. T-cell functions also depend on co-signaling receptors, inhibitory or stimulatory, known as immune checkpoints, including cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed death-1 (PD-1). Here we analyzed the T-cell phenotype focusing on immune checkpoints and activation markers in chronic lymphocytic leukemia patients (n=80) with different clinical characteristics and compared them to healthy controls. In general, patients had higher absolute numbers of CD3+cells and the CD8+subset was particularly expanded in previously treated patients. Progressive patients had higher numbers of CD4+and CD8+cells expressing PD-1 compared to healthy controls, which was more pronounced in previously treated patients (P=0.0003 andP=0.001, respectively). A significant increase in antigen-experienced T cells was observed in patients within both the CD4+and CD8+subsets, with a significantly higher PD-1 expression. Higher numbers of CD4+and CD8+cells with intracellular CTLA-4 were observed in patients, as well as high numbers of proliferating (Ki67+) and activated (CD69+) CD4+and CD8+cells, more pronounced in patients with active disease. The numbers of Th1, Th2, Th17 and regulatory T cells were substantially increased in patients compared to controls (P<0.05), albeit decreasing to low levels in pre-treated patients. In conclusion, chronic lymphocytic leukemia T cells display increased expression of immune checkpoints, abnormal subset distribution, and a higher proportion of proliferating cells compared to healthy T cells. Disease activity and previous treatment shape the T-cell profile of chronic lymphocytic leukemia patients in different ways.
authors.affiliation: Immune and Gene Therapy Laboratory, Department of Oncology & Pathology, Cancer Centre Karolinska, Karolinska Institutet, Stockholm, Sweden marzia.palma@karolinska.se.|Department of Hematology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Marzia
authors.initials: M
authors.lastname: Palma
authors.affiliation: Immune and Gene Therapy Laboratory, Department of Oncology & Pathology, Cancer Centre Karolinska, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Giusy
authors.initials: G
authors.lastname: Gentilcore
authors.affiliation: Immune and Gene Therapy Laboratory, Department of Oncology & Pathology, Cancer Centre Karolinska, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kia
authors.initials: K
authors.lastname: Heimersson
authors.affiliation: Immune and Gene Therapy Laboratory, Department of Oncology & Pathology, Cancer Centre Karolinska, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Fariba
authors.initials: F
authors.lastname: Mozaffari
authors.affiliation: Immune and Gene Therapy Laboratory, Department of Oncology & Pathology, Cancer Centre Karolinska, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Barbro
authors.initials: B
authors.lastname: Näsman-Glaser
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Young
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden.
authors.forename: Richard
authors.initials: R
authors.lastname: Rosenquist
authors.affiliation: Immune and Gene Therapy Laboratory, Department of Oncology & Pathology, Cancer Centre Karolinska, Karolinska Institutet, Stockholm, Sweden.|Department of Hematology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Lotta
authors.initials: L
authors.lastname: Hansson
authors.affiliation: Immune and Gene Therapy Laboratory, Department of Oncology & Pathology, Cancer Centre Karolinska, Karolinska Institutet, Stockholm, Sweden.|Department of Hematology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Österborg
authors.affiliation: Immune and Gene Therapy Laboratory, Department of Oncology & Pathology, Cancer Centre Karolinska, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Håkan
authors.initials: H
authors.lastname: Mellstedt
mesh_terms: D000368:Aged; D015415:Biomarkers; D014408:Biomarkers, Tumor; D060908:CTLA-4 Antigen / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D002869:Chromosome Aberrations; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D056747:Immunomodulation / Q000235:genetics*; D016130:Immunophenotyping; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology* / Q000628:therapy; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; D014408:Biomarkers, Tumor; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D061026:Programmed Cell Death 1 Receptor; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9