Abstract

Therapeutic Effects of anti-LAP Antibody in Different Cancer Models

Galina Gabriely, Instructor, Brigham and Women's Hospital

A major advance in the treatment of cancer has been the development of immunotherapy that acts by counteracting the suppressive environment established by the tumor. Although it is known that regulatory T cells contribute to cancer immune suppression, there are few surface molecules on T_regs that can specifically be targeted for the treatment of cancer. We identified a novel T_reg population characterized by the expression of surface latency-associated peptide (LAP) which is a regulator of TGF-ß, a potent immunosuppressive cytokine. An increase in LAP⁺CD4⁺ T cells has been reported in human cancer, including head and neck and colorectal cancer. To study the regulatory role of LAP⁺CD4⁺ T cells in mouse models of cancer we developed a murine monoclonal anti-LAP antibody. We found that treatment with anti-LAP reduces tumor growth and increases survival in various cancer models, including colon carcinoma, glioblastoma and melanoma. Anti-LAP antibody is able to block TGF-ß release from cells expressing LAP and also reduces both the number and suppressive abilities of tumor-associated LAP⁺CD4⁺ regulatory T cells. Anti-LAP treatment triggers a profound peripheral immune response by acting on both innate and adaptive parts of the immune system. These changes are associated with an increased infiltration of cytotoxic CD8⁺ T lymphocytes into tumors. Based on the TCGA data analysis, the expression of LAP-associated genes correlates inversely with patient survival in a number of cancers that include, among others, glioblastoma, colon carcinoma and melanoma. In conclusion, anti-LAP antibody as a monotherapy or combined with conventional anti-tumor modalities represents a novel immunotherapeutic approach for cancer treatment.