Oncotarget

Research Papers:

The immune checkpoint molecules PD-1, PD-L1, TIM-3 and LAG-3 in diffuse large B-cell lymphoma

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Oncotarget. 2019; 10:2030-2040. https://doi.org/10.18632/oncotarget.26771

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Benjamin J. Chen, Ravi Dashnamoorthy, Pallavi Galera, Vladislav Makarenko, Hong Chang, Srimoyee Ghosh, Andrew M. Evens

Abstract

Benjamin J. Chen1, Ravi Dashnamoorthy2, Pallavi Galera1, Vladislav Makarenko1, Hong Chang3, Srimoyee Ghosh4 and Andrew M. Evens2

1 Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA

2 Division of Blood Disorders, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA

3 Institute for Clinical Research and Health Policy Studies and the Biostatistics, Epidemiology, and Research Design (BERD) Center, Tufts Medical Center, Boston, MA, USA

4 Tesaro, Waltham, MA, USA

Correspondence to:

Benjamin J. Chen, email: Benjamin.chen@umassmemorial.org

Keywords: lymphoma; immunotherapy; immune checkpoint; TIM-3; LAG-3

Received: February 07, 2019     Accepted: February 21, 2019     Published: March 12, 2019

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.