Layal El Halabi1, Julien Adam2, Pauline Gravelle3, Virginie Marty4, Alina Danu1, Julien Lazarovici1, Vincent Ribrag1, Jacques Bosq2, Valérie Camara-Clayette5, Camille Laurent3, David Ghez6. 1. Department of Hematology, Gustave Roussy, Villejuif, France. 2. Department of Pathology, Gustave Roussy, Villejuif, France. 3. Pathology and Cytology Department, Centre Hospitalo-Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France; Centre de Recherche en Cancerologie de Toulouse, INSERM, UMR1037, Institut Carnot Lymphome CALYM, Toulouse, France. 4. Plateforme de Pathologie Expérimentale et TRAnslationnelle (PETRA), AMMICA INSERM US23/UMS CNRS3655, Gustave Roussy, Villejuif, France. 5. Plateforme AMMICA, Recherche Translationnelle Hématologie, INSERM US23/CNRS UMS3655, Gustave Roussy, Villejuif, France; Université Paris Sud, Institut de Cancérologie, Gustave Roussy, Villejuif, France. 6. Department of Hematology, Gustave Roussy, Villejuif, France. Electronic address: david.ghez@gustaveroussy.fr.
Abstract
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.
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.