Role of LAP positive immune cells in glioblastoma pathogenesis

Brigham And Women'S Hospital, Boston MA

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Abstract

DESCRIPTION (provided by applicant): 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.