Expression of the Immune Checkpoint Regulators LAG-3 and TIM-3 in Classical Hodgkin Lymphoma

Programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) blocking agents are used in relapsed/ refractory classical Hodgkin lymphoma (HL), while other immune checkpoints such as lymphocyte-activation gene 3 (LAG-3) and T-cell immunoglobulin and mucin-domain containing 3 (TIM-3) may also play a role. By performing immunohistochemistry on 57 biopsy samples, we found that TIM-3 was expressed by Hodgkin and Reed/Sternberg cells in 36% of the cases, and LAG-3 and TIM-3 were widely expressed in the tumor microenvironment. LAG-3 and TIM-3 may constitute therapeutic targets in the treatment of HL. Introduction: The role of the programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) axis is well established in classical Hodgkin lymphoma (HL), where PD-1 blockade demonstrated spectacular efficacy in relapsed/ refractory disease. However, little is known about the frequency and cellular distribution of other immune checkpoints in HL samples. Patients and Methods: Using immunohistochemistry, we investigated, along with PD-L1 and PD-1, the expression of lymphocyte-activation gene 3 (LAG-3) and T-cell immunoglobulin and mucin-domain containing 3 (TIM-3) in 57 biopsy samples of patients with classical HL. Results: Hodgkin and Reed/Sternberg (HRS) cells were strongly positive for PD-L1 in nearly all cases. HRS cells were TIM-3 positive in 36% of samples, whereas LAG-3 was rarely expressed (5.2%). In the microenvironment, PD-1, LAG-3, and TIM-3 were expressed by >= 5% of cells in 65%, 98%, and 96% of cases, respectively. T-cell rosettes surrounding HRS cells consisted of CD4(+) FoxP3 helper T cells expressing both PD-1 and LAG-3, with a variable expression of TIM-3. Conclusion: This study demonstrates for the first time that LAG-3 and TIM-3 are nearly always expressed in the microenvironment of classical HL. This may constitute the basis for targeting LAG-3 or TIM-3 in combination with anti-PD-1 antibodies in the treatment of relapsed/refractory HL. (C) 2020 Elsevier Inc. All rights reserved.

Automated summary

In classical Hodgkin lymphoma, PD-1/PD-L1 blockade has shown great efficacy, and the study found that TIM-3 is frequently expressed in the tumor microenvironment. LAG-3 and TIM-3 may be potential therapeutic targets in the treatment of HL.