Among the various molecules that regulate T cell function, Lymphocyte Activation Gene 3 (LAG-3) has garnered significant recent interest. LAG-3 is a CD4 homolog originally cloned in 1990. The gene for LAG-3 lies adjacent to the gene for CD4 on human chromosome 12 (12p13) and is approximately 20% identical to the CD4 gene. LAG-3 is expressed on B cells, NK cells, tumor infiltrating lymphocytes (TIL), and a subset of dendritic cells. Recently, we showed that LAG-3 was relatively over-expressed on HA- specific transgenic T cells rendered anergic in vivo by encounter with cognate self- antigen. In this system, tolerized T cells display regulatory function both in vitro and in vivo;and regulatory activity could be functionally blocked with a LAG-3 specific monoclonal antibody. By transducing naive CD4 T cells with a full length LAG-3 construct, we could confer in vitro regulatory activity. Studies in humans have demonstrated increased LAG-3 expression on tumor-infiltrating FoxP3+ regulatory T cells. In addition to CD4 T cells, activated CD8 T cells increase LAG-3 expression in response to antigen stimulation, and LAG-3 positive CD8 T cells frequently infiltrate tumors in cancer patients. Observations using LAG-3 knockout mice demonstrate that CD8 T cells undergo enhanced homeostatic proliferation in vivo if LAG-3 is absent. Studies using human PBMC also suggest a negative regulatory role for LAG-3 on CD8 T cell expansion, as LAG-3 antibody blockade combined with superantigen stimulation results in increased proliferation CD8 T cells compared to superantigen alone. We have generated significant preliminary and published data suggesting that LAG-3 blockade can alter the immune response to both autochthonous and implanted tumors and suggest that LAG-3 blockade may eventually play a significant role in tumor immunotherapy.

Public Health Relevance

LAG-3 is a molecule on the surface of some white blood cells known as T cells;T cells are responsible for fighting infection, and in some cases can help to eliminate tumors. Since LAG-3 on T cells inhibits their function, we propose to improve the immune response to cancer by blocking LAG-3 with small proteins known as monoclonal antibodies. The overall goal of these studies is to understand how LAG-3 works, and then to use this information to target LAG-3 in an effort to improve immune treatments for cancer patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Cancer Immunopathology and Immunotherapy Study Section (CII)
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Mccarthy, Susan A
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Johns Hopkins University
Internal Medicine/Medicine
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United States
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Shen, Ying-Chun; Ghasemzadeh, Ali; Kochel, Christina M et al. (2018) Combining intratumoral Treg depletion with androgen deprivation therapy (ADT): preclinical activity in the Myc-CaP model. Prostate Cancer Prostatic Dis 21:113-125
LaFleur, Martin W; Muroyama, Yuki; Drake, Charles G et al. (2018) Inhibitors of the PD-1 Pathway in Tumor Therapy. J Immunol 200:375-383
Muroyama, Yuki; Nirschl, Thomas R; Kochel, Christina M et al. (2017) Stereotactic Radiotherapy Increases Functionally Suppressive Regulatory T Cells in the Tumor Microenvironment. Cancer Immunol Res 5:992-1004
Ghasemzadeh, Ali; Bivalacqua, Trinity J; Hahn, Noah M et al. (2016) New Strategies in Bladder Cancer: A Second Coming for Immunotherapy. Clin Cancer Res 22:793-801
Attard, Gerhardt; Parker, Chris; Eeles, Ros A et al. (2016) Prostate cancer. Lancet 387:70-82
Jackson, Christopher M; Kochel, Christina M; Nirschl, Christopher J et al. (2016) Systemic Tolerance Mediated by Melanoma Brain Tumors Is Reversible by Radiotherapy and Vaccination. Clin Cancer Res 22:1161-72
Martin, A M; Nirschl, T R; Nirschl, C J et al. (2015) Paucity of PD-L1 expression in prostate cancer: innate and adaptive immune resistance. Prostate Cancer Prostatic Dis 18:325-32
Durham, Nicholas M; Nirschl, Christopher J; Jackson, Christopher M et al. (2014) Lymphocyte Activation Gene 3 (LAG-3) modulates the ability of CD4 T-cells to be suppressed in vivo. PLoS One 9:e109080
Nirschl, Christopher J; Drake, Charles G (2013) Molecular pathways: coexpression of immune checkpoint molecules: signaling pathways and implications for cancer immunotherapy. Clin Cancer Res 19:4917-24
Jackson, Christopher M; Flies, Dallas B; Mosse, Claudio A et al. (2013) Strain-specific induction of experimental autoimmune prostatitis (EAP) in mice. Prostate 73:651-6

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