Lymphocyte activation gene 3: a novel therapeutic target in chronic lymphocytic leukemia.
A novel therapeutic approach in cancer, attempting to stimulate host anti-tumor immunity, involves blocking of immune checkpoints. Lymphocyte activation gene 3 (LAG3) is an immune checkpoint receptor expressed on activated/exhausted T cells. When engaged by the major histocompatibility complex (MHC) class II molecules, LAG3 negatively regulates T-cell function, thereby contributing to tumor escape. Intriguingly, a soluble LAG3 variant activates both immune and malignant MHC class II-presenting cells. In the study herein, we examined the role of LAG3 in the pathogenesis of chronic lymphocytic leukemia, an MHC class II-presenting malignancy, and show that chronic lymphocytic leukemia cells express and secrete LAG3. High levels of surface and soluble LAG3 were associated with the unmutated immunoglobulin variable heavy chain leukemic subtype and a shorter median time from diagnosis to first treatment. Utilizing a mechanism mediated through MHC class II engagement, recombinant soluble LAG3-Ig fusion protein, LAG3-Fc, activated chronic lymphocytic leukemia cells, induced anti-apoptotic pathways and protected the cells from spontaneous apoptosis, effects mediated by SYK, BTK and MAPK signaling. Moreover, LAG3 blocking antibody enhancedin vitroT-cell activation. Our data suggest that soluble LAG3 promotes leukemic cell activation and anti-apoptotic effects through its engagement with MHC class II. Furthermore, MHC class II-presenting chronic lymphocytic leukemia cells may affect LAG3-presenting T cells and impose immune exhaustion on their microenvironment; hence, blocking LAG3-MHC class II interactions is a potential therapeutic target in chronic lymphocytic leukemia.
Department of Hematology, Tel Aviv Sourasky Medical Center, Israel.
Mika
M
Shapiro
Department of Hematology, Tel Aviv Sourasky Medical Center, Israel yairh@tlvmc.gov.il.|Sackler Faculty of Medicine, Tel Aviv University, Israel.
Yair
Y
Herishanu
Department of Hematology, Tel Aviv Sourasky Medical Center, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Israel.
Ben-Zion
BZ
Katz
Department of Hematology, Tel Aviv Sourasky Medical Center, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Israel.
Nili
N
Dezorella
Hematology Branch, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Clare
C
Sun
Department of Hematology, Tel Aviv Sourasky Medical Center, Israel.
Sigi
S
Kay
Hadassah University Hospital, Jerusalem, Israel.
Aaron
A
Polliack
Department of Hematology, Tel Aviv Sourasky Medical Center, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Israel.
Irit
I
Avivi
Hematology Branch, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Adrian
A
Wiestner
Department of Hematology, Tel Aviv Sourasky Medical Center, Israel.
Chava
C
Perry
D019138:Antibodies, Blocking / Q000276:immunology / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D058990:Molecular Targeted Therapy / Q000379:methods; D011485:Protein Binding / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D000093322:Lymphocyte Activation Gene 3 Protein
D019138:Antibodies, Blocking; D015703:Antigens, CD; D000949:Histocompatibility Antigens Class II; D000093322:Lymphocyte Activation Gene 3 Protein; C000720326:Lag3 protein, human; C000720328:soluble LAG-3 protein, human