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

Colm Keane; Soi C. Law; Clare Gould; Simone Birch; Muhammed B. Sabdia; Lilia Merida de Long; Gayathri Thillaiyampalam; Emad Abro; Joshua W. Tobin; Xiaohong Tan; Zijun Y. Xu-Monette; Ken H. Young; Grace Gifford; Sara Gabreilli; William S. Stevenson; Anthony Gill; Dipti Talaulikar; Sanjiv Jain; Annette Hernandez; Sarah Jane Halliday; Robert Bird; Donna Cross; Mark Hertzberg; Maher K. Gandhi

doi:10.1182/bloodadvances.2019001390

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

Colm Keane^*, Soi C. Law, Clare Gould, Simone Birch, Muhammed B. Sabdia, Lilia Merida de Long, Gayathri Thillaiyampalam, Emad Abro, Joshua W. Tobin, Xiaohong Tan, Zijun Y. Xu-Monette, Ken H. Young, Grace Gifford, Sara Gabreilli, William S. Stevenson, Anthony Gill, Dipti Talaulikar, Sanjiv Jain, Annette Hernandez, Sarah Jane HallidayRobert Bird, Donna Cross, Mark Hertzberg, Maher K. Gandhi

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

74 Citations (Scopus)

Abstract

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 CD4¹ regulatory T cells (Tregs) and was also highly expressed on CD8¹ T cells compared with CD4¹ non-Tregs (both P 5 .008). LAG3^high 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 5 .03). LAG3^high 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-L1^high were ﬁvefold more likely to be LAG3^high (P , .0001). Patients who were LAG3^high/PD-L1^high had an inferior progression-free survival (P 5 .011) and overall survival (P 5 .005) compared with patients who were LAG3^low/PD-L1^high. Digital spatial protein analysis conﬁrms LAG3 expression on T cells and, surprisingly, tumor-associated macrophages (TAMs) at higher levels than found on CD20¹ B cells in the tumor microenvironment. LAG3 is frequently expressed on CD4¹ Tregs and CD8¹ 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. LAG3^high expression is associated with poor outcome independent of conventional prognosticators.

Original language	English
Pages (from-to)	1367-1377
Number of pages	11
Journal	Blood advances
Volume	4
Issue number	7
DOIs	https://doi.org/10.1182/bloodadvances.2019001390
Publication status	Published - 14 Apr 2020

Access to Document

10.1182/bloodadvances.2019001390

Cite this

Keane, C., Law, S. C., Gould, C., Birch, S., Sabdia, M. B., de Long, L. M., Thillaiyampalam, G., Abro, E., Tobin, J. W., Tan, X., Xu-Monette, Z. Y., Young, K. H., Gifford, G., Gabreilli, S., Stevenson, W. S., Gill, A., Talaulikar, D., Jain, S., Hernandez, A., ... Gandhi, M. K. (2020). LAG3: A novel immune checkpoint expressed by multiple lymphocyte subsets in diffuse large B-cell lymphoma. Blood advances, 4(7), 1367-1377. https://doi.org/10.1182/bloodadvances.2019001390

@article{42d88ffc0cd04dbeb0d3ed667bc11d07,

title = "LAG3: A novel immune checkpoint expressed by multiple lymphocyte subsets in diffuse large B-cell lymphoma",

abstract = "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 CD41 regulatory T cells (Tregs) and was also highly expressed on CD81 T cells compared with CD41 non-Tregs (both P 5 .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 5 .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 5 .011) and overall survival (P 5 .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 CD201 B cells in the tumor microenvironment. LAG3 is frequently expressed on CD41 Tregs and CD81 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.",

author = "Colm Keane and Law, {Soi C.} and Clare Gould and Simone Birch and Sabdia, {Muhammed B.} and {de Long}, {Lilia Merida} and Gayathri Thillaiyampalam and Emad Abro and Tobin, {Joshua W.} and Xiaohong Tan and Xu-Monette, {Zijun Y.} and Young, {Ken H.} and Grace Gifford and Sara Gabreilli and Stevenson, {William S.} and Anthony Gill and Dipti Talaulikar and Sanjiv Jain and Annette Hernandez and Halliday, {Sarah Jane} and Robert Bird and Donna Cross and Mark Hertzberg and Gandhi, {Maher K.}",

note = "Publisher Copyright: {\textcopyright} 2020 by The American Society of Hematology",

year = "2020",

month = apr,

day = "14",

doi = "10.1182/bloodadvances.2019001390",

language = "English",

volume = "4",

pages = "1367--1377",

journal = "Blood advances",

issn = "2473-9529",

publisher = "Elsevier B.V.",

number = "7",

}

Keane, C, Law, SC, Gould, C, Birch, S, Sabdia, MB, de Long, LM, Thillaiyampalam, G, Abro, E, Tobin, JW, Tan, X, Xu-Monette, ZY, Young, KH, Gifford, G, Gabreilli, S, Stevenson, WS, Gill, A, Talaulikar, D, Jain, S, Hernandez, A, Halliday, SJ, Bird, R, Cross, D, Hertzberg, M & Gandhi, MK 2020, 'LAG3: A novel immune checkpoint expressed by multiple lymphocyte subsets in diffuse large B-cell lymphoma', Blood advances, vol. 4, no. 7, pp. 1367-1377. https://doi.org/10.1182/bloodadvances.2019001390

TY - JOUR

T1 - LAG3

T2 - A novel immune checkpoint expressed by multiple lymphocyte subsets in diffuse large B-cell lymphoma

AU - Keane, Colm

AU - Law, Soi C.

AU - Gould, Clare

AU - Birch, Simone

AU - Sabdia, Muhammed B.

AU - de Long, Lilia Merida

AU - Thillaiyampalam, Gayathri

AU - Abro, Emad

AU - Tobin, Joshua W.

AU - Tan, Xiaohong

AU - Xu-Monette, Zijun Y.

AU - Young, Ken H.

AU - Gifford, Grace

AU - Gabreilli, Sara

AU - Stevenson, William S.

AU - Gill, Anthony

AU - Talaulikar, Dipti

AU - Jain, Sanjiv

AU - Hernandez, Annette

AU - Halliday, Sarah Jane

AU - Bird, Robert

AU - Cross, Donna

AU - Hertzberg, Mark

AU - Gandhi, Maher K.

PY - 2020/4/14

Y1 - 2020/4/14

N2 - 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 CD41 regulatory T cells (Tregs) and was also highly expressed on CD81 T cells compared with CD41 non-Tregs (both P 5 .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 5 .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 5 .011) and overall survival (P 5 .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 CD201 B cells in the tumor microenvironment. LAG3 is frequently expressed on CD41 Tregs and CD81 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.

AB - 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 CD41 regulatory T cells (Tregs) and was also highly expressed on CD81 T cells compared with CD41 non-Tregs (both P 5 .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 5 .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 5 .011) and overall survival (P 5 .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 CD201 B cells in the tumor microenvironment. LAG3 is frequently expressed on CD41 Tregs and CD81 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.

UR - http://www.scopus.com/inward/record.url?scp=85083742061&partnerID=8YFLogxK

U2 - 10.1182/bloodadvances.2019001390

DO - 10.1182/bloodadvances.2019001390

M3 - Article

SN - 2473-9529

VL - 4

SP - 1367

EP - 1377

JO - Blood advances

JF - Blood advances

IS - 7

ER -

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

Abstract

Access to Document

Other files and links

Fingerprint

Cite this