UMMS Affiliation
Department of Pathology
Publication Date
2019-03-12
Document Type
Article
Disciplines
Cancer Biology | Cells | Hemic and Immune Systems | Hemic and Lymphatic Diseases | Immune System Diseases | Immunoprophylaxis and Therapy | Neoplasms
Abstract
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.
Keywords
LAG-3, TIM-3, immune checkpoint, immunotherapy, lymphoma
Rights and Permissions
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.
DOI of Published Version
10.18632/oncotarget.26771
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
Journal/Book/Conference Title
Oncotarget
Related Resources
PubMed ID
31007846
Repository Citation
Chen, Benjamin J.; Dashnamoorthy, Ravi; Galera, Pallavi; Makarenko, Vladislav; Chang, Hong; Ghosh, Srimoyee; and Evens, Andrew M., "The immune checkpoint molecules PD-1, PD-L1, TIM-3 and LAG-3 in diffuse large B-cell lymphoma" (2019). Open Access Articles. 3809.
https://escholarship.umassmed.edu/oapubs/3809
Creative Commons License
This work is licensed under a Creative Commons Attribution 3.0 License.
Included in
Cancer Biology Commons, Cells Commons, Hemic and Immune Systems Commons, Hemic and Lymphatic Diseases Commons, Immune System Diseases Commons, Immunoprophylaxis and Therapy Commons, Neoplasms Commons