The immune checkpoint molecules PD-1, PD-L1, TIM-3 and LAG-3 in diffuse large B-cell lymphoma
Authors
Chen, Benjamin J.Dashnamoorthy, Ravi
Galera, Pallavi
Makarenko, Vladislav
Chang, Hong
Ghosh, Srimoyee
Evens, Andrew M.
UMass Chan Affiliations
Department of PathologyDocument Type
Journal ArticlePublication Date
2019-03-12Keywords
LAG-3TIM-3
immune checkpoint
immunotherapy
lymphoma
Cancer Biology
Cells
Hemic and Immune Systems
Hemic and Lymphatic Diseases
Immune System Diseases
Immunoprophylaxis and Therapy
Neoplasms
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Show full item recordAbstract
Signaling through immune checkpoint receptors may lead to T-cell exhaustion and function as immune escape mechanisms in cancer. For diffuse large B-cell lymphoma (DLBCL), the mechanistic and prognostic importance of these markers on tumor cells and the tumor microenvironment remains unclear. We determined the immunohistochemical expression of PD-1, PD-L1, TIM-3, and LAG-3 on tumor cells and on tumor infiltrating lymphocytes (TILs) among 123 DLBCL patients. TIM-3 showed positive staining on tumor cells in 39% of DLBCL cases and PD-L1 expression was noted in 15% of cases. Both PD-1 and LAG-3 were positive on tumor cells in a minority of DLBCL cases (8.3% and 7.5%, respectively), but were more widely expressed on TILs in a correlated manner. With median follow-up of 44 months (n = 70, range 5-85), 4-year progression-free survival (PFS) and overall survival (OS) rates were significantly inferior among DLBCL patients with high vs low/negative TIM-3 expression (PFS: 23% [95% CI 7% to 46%] vs 60% [95% CI 43% to 74%], respectively, P = 0.008; OS: 30% [95% CI 10% to 53%] vs 74% [95% CI 58% to 85%], respectively, P = 0.006). Differences in OS remained significant when controlling for International Prognostic Index in Cox regression analyses (HR 3.49 [95% CI 1.40-6.15], P = 0.007). In addition, we observed that co-culture of DLBCL cell lines with primed T cells in the presence of anti-LAG-3 and anti-TIM-3 induced potent dose-dependent increases in in vitro cell death via AcellaTox and IL-2 ELISA assays, suggesting potent anti-tumor activity of these compounds.Source
Oncotarget. 2019 Mar 12;10(21):2030-2040. doi: 10.18632/oncotarget.26771. eCollection 2019 Mar 12. Link to article on publisher's site
DOI
10.18632/oncotarget.26771Permanent Link to this Item
http://hdl.handle.net/20.500.14038/41013PubMed ID
31007846Related Resources
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Copyright : © 2019 Chen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Distribution License
http://creativecommons.org/licenses/by/3.0/ae974a485f413a2113503eed53cd6c53
10.18632/oncotarget.26771
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Except where otherwise noted, this item's license is described as Copyright : © 2019 Chen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source
are credited.