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

Area of Science:

• Immunology
• Oncology
• Pathology

Background:

• Immune checkpoint receptors (ICRs) like PD-1, PD-L1, TIM-3, and LAG-3 are implicated in cancer immune escape.
• The role and prognostic significance of these ICRs in diffuse large B-cell lymphoma (DLBCL) are not fully understood.

Purpose of the Study:

• To investigate the expression of PD-1, PD-L1, TIM-3, and LAG-3 in DLBCL.
• To determine the prognostic value of these markers in DLBCL patients.
• To explore the therapeutic potential of targeting LAG-3 and TIM-3.

Main Methods:

• Immunohistochemical analysis of PD-1, PD-L1, TIM-3, and LAG-3 on tumor cells and tumor-infiltrating lymphocytes (TILs) in 123 DLBCL patients.
• Survival analysis (progression-free survival and overall survival) correlated with marker expression.
• In vitro co-culture assays using DLBCL cell lines, primed T cells, and anti-LAG-3/anti-TIM-3 antibodies.

Main Results:

• TIM-3 was expressed on tumor cells in 39% of DLBCL cases, and PD-L1 in 15%.
• PD-1 and LAG-3 were less frequent on tumor cells but widely expressed on TILs.
• High TIM-3 expression on tumor cells correlated with significantly inferior 4-year progression-free survival (PFS) and overall survival (OS) (P=0.008 and P=0.006, respectively).
• This association remained significant after controlling for the International Prognostic Index (HR 3.49, P=0.007).
• In vitro, anti-LAG-3 and anti-TIM-3 antibodies induced dose-dependent cell death in DLBCL cells.

Conclusions:

• TIM-3 expression on DLBCL tumor cells is a significant negative prognostic factor.
• PD-1 and LAG-3 are more prevalent on TILs than tumor cells in DLBCL.
• Targeting LAG-3 and TIM-3 demonstrates promising in vitro anti-tumor activity for DLBCL.