The suppression of the immune system is one of the major obstacles in the treatment of glioblastoma (GBM). Regulatory immune cells, such as FoxP3+ T lymphocytes and suppressive myeloid cells play a significant role in this process. LAP+ CD4+ T lymphocytes were recently described as superior regulatory cells in colorectal cancer and we found that other LAP+ immune cells may also have regulatory functions. Latency-associated peptide (LAP) is a derivative of the TGF-? gene and TGF-? is strongly implicated in GBM pathogenesis. Based on TCGA (The Cancer Genome Atlas) data, we found that TGF-? mRNA expression negatively correlates with human patient survival. We also found that different LAP+ immune cells infiltrate intracranial GBM, including subsets of both ?? and ??+ T cells, macrophages and dendritic cells in a mouse model. Treatment of mice bearing sub-cutaneous GBM with anti-LAP antibodies led to elimination of GBM growth and was associated with a reduction of FoxP3+ and LAP+ T cells and up-regulation of the Th1 and cytotoxic T cell responses. Based on these observations, we hypothesize that cells expressing LAP suppress GBM-specific immunity and neutralization with anti-LAP antibodies will activate a tumoricidal immune response. In this project, we propose to study the role of neutralizing antibodies against LAP in overcoming the immunosuppression associated with GBM.
Our specific aims are:
Specific Aim 1 : Investigate the immunosuppressive role of LAP in GBM. We propose to 1) determine the levels of LAP expression on immune cells in normal and GBM conditions in mouse and human;2) define the phenotype of LAP+ immune cells infiltrating intracranial GBM isolated at different stages of disease progression in mouse and human;3) perform functional analysis of LAP+ regulatory immune cells isolated from intracranial GBM.
Specific Aim 2 : Evaluate the therapeutic potential of anti-LAP antibodies in the treatment of a GBM intracranial mouse model. We propose to 1) characterize the effects of anti-LAP antibodies on the immune response in naive mice and mice bearing intracranial GBM;2) assess the therapeutic value of anti-LAP antibodies in the experimental GBM models.

Public Health Relevance

Regulatory T cells play an important role in glioblastoma (GBM) progression by suppressing the anti- tumor defense of the immune system. However, the mechanisms of their pathogenicity and the role of other immune cells in the suppression of the immune system are poorly understood. We found that targeting a specific subset of latency-associated peptide (LAP) positive regulatory immune cells has the potential to activate the immune response against GBM leading to reduction of tumor growth. In this project, we propose to study the role of LAP in GBM progression, and assess the value of anti-LAP antibodies in the treatment of glioblastoma and other brain tumors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS090163-01
Application #
8807222
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Fountain, Jane W
Project Start
2014-09-30
Project End
2016-08-31
Budget Start
2014-09-30
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$265,438
Indirect Cost
$115,438
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115