LAG3: a novel immune checkpoint expressed by multiple lymphocyte subsets in diffuse large B-cell lymphoma.

Autor:	Keane C; Mater Research, University of Queensland, Translational Research Institute, Brisbane, QLD, Australia.; Princess Alexandra Hospital, Brisbane, QLD, Australia., Law SC; Mater Research, University of Queensland, Translational Research Institute, Brisbane, QLD, Australia., Gould C; University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia., Birch S; Pathology Queensland, Princess Alexandra Hospital, Brisbane, QLD, Australia., Sabdia MB; Mater Research, University of Queensland, Translational Research Institute, Brisbane, QLD, Australia., Merida de Long L; Mater Research, University of Queensland, Translational Research Institute, Brisbane, QLD, Australia., Thillaiyampalam G; University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, QLD, Australia., Abro E; Princess Alexandra Hospital, Brisbane, QLD, Australia., Tobin JW; Mater Research, University of Queensland, Translational Research Institute, Brisbane, QLD, Australia., Tan X; Division of Hematopathology, Department of Pathology, Duke University School of Medicine, Durham, NC., Xu-Monette ZY; Division of Hematopathology, Department of Pathology, Duke University School of Medicine, Durham, NC., Young KH; Division of Hematopathology, Department of Pathology, Duke University School of Medicine, Durham, NC., Gifford G; Kolling Institute of Medical Research, University of Sydney, Sydney, NSW, Australia.; Department of Haematology and Transfusion Medicine, Royal North Shore Hospital, Sydney, NSW, Australia., Gabreilli S; Kolling Institute of Medical Research, University of Sydney, Sydney, NSW, Australia.; Department of Haematology and Transfusion Medicine, Royal North Shore Hospital, Sydney, NSW, Australia., Stevenson WS; Kolling Institute of Medical Research, University of Sydney, Sydney, NSW, Australia.; Department of Haematology and Transfusion Medicine, Royal North Shore Hospital, Sydney, NSW, Australia., Gill A; NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW, Australia., Talaulikar D; Canberra Hospital, Canberra, ACT, Australia.; Australia National University Medical School, Canberra, ACT, Australia; and., Jain S; Canberra Hospital, Canberra, ACT, Australia.; Australia National University Medical School, Canberra, ACT, Australia; and., Hernandez A; Pathology Queensland, Princess Alexandra Hospital, Brisbane, QLD, Australia., Halliday SJ; Pathology Queensland, Princess Alexandra Hospital, Brisbane, QLD, Australia., Bird R; Princess Alexandra Hospital, Brisbane, QLD, Australia.; Pathology Queensland, Princess Alexandra Hospital, Brisbane, QLD, Australia., Cross D; Pathology Queensland, Princess Alexandra Hospital, Brisbane, QLD, Australia., Hertzberg M; Prince of Wales Hospital, Sydney, NSW, Australia., Gandhi MK; Mater Research, University of Queensland, Translational Research Institute, Brisbane, QLD, Australia.; Princess Alexandra Hospital, Brisbane, QLD, Australia.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2020 Apr 14; Vol. 4 (7), pp. 1367-1377.
DOI:	10.1182/bloodadvances.2019001390
Abstrakt:	Blockade of the PD-1 axis has modest efficacy in diffuse large B-cell lymphoma (DLBCL), but data regarding LAG3 are sparse. The impact of LAG3 digital gene expression was tested in 309 patients with DLBCL treated with standard chemoimmunotherapy. Cellular distribution of LAG3 protein was determined by immunohistochemistry and flow cytometry. In tumor-infiltrating lymphocytes (TILs), LAG3 expression was highest on CD4+ regulatory T cells (Tregs) and was also highly expressed on CD8+ T cells compared with CD4+ non-Tregs (both P = .008). LAG3high TILs were enriched in PD-1 and TIM-3. LAG3 was also expressed on a proportion of malignant B cells, and these patients had significantly higher LAG3 messenger RNA in their biopsies (P = .03). LAG3high gene expression was associated with inferior survival in discovery/validation cohorts, independent of cell of origin and the international prognostic index. Patients who were PD-L1high were fivefold more likely to be LAG3high (P < .0001). Patients who were LAG3high/PD-L1high had an inferior progression-free survival (P = .011) and overall survival (P = .005) compared with patients who were LAG3low/PD-L1high. Digital spatial protein analysis confirms LAG3 expression on T cells and, surprisingly, tumor-associated macrophages (TAMs) at higher levels than found on CD20+ B cells in the tumor microenvironment. LAG3 is frequently expressed on CD4+ Tregs and CD8+ TILs, typically with other immune checkpoints, and is also present in a proportion of malignant B cells in DLBCL and in areas enriched for TAMs. LAG3high expression is associated with poor outcome independent of conventional prognosticators. (© 2020 by The American Society of Hematology.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu