Gabriely et al. targeted latency-associated peptide (LAP) with an anti-LAP antibody, which both reduces the number of LAP+ T cells, and blocks the release of immune-suppressive TGF-β. Treatment with anti-LAP improved dendritic cell phenotypes, increased CD8+ T cell responses and tumor infiltration, and reduced tolerogenic CD103+CD8+ T cells, ultimately decreasing tumor growth. Anti-LAP antibody also enhanced the antitumor effects of a dendritic cell vaccine.
Regulatory T cells (Tregs) promote cancer by suppressing antitumor immune responses. We found that anti-LAP antibody, which targets the latency-associated peptide (LAP)/transforming growth factor-beta (TGF-beta) complex on Tregs and other cells, enhances antitumor immune responses and reduces tumor growth in models of melanoma, colorectal carcinoma, and glioblastoma. Anti-LAP decreases LAP+ Tregs, tolerogenic dendritic cells, and TGF-beta secretion and is associated with CD8+ T cell activation. Anti-LAP increases infiltration of tumors by cytotoxic CD8+ T cells and reduces CD103+ CD8 T cells in draining lymph nodes and the spleen. We identified a role for CD103+ CD8 T cells in cancer. Tumor-associated CD103+ CD8 T cells have a tolerogenic phenotype with increased expression of CTLA-4 and interleukin-10 and decreased expression of interferon-gamma, tumor necrosis factor-alpha, and granzymes. Adoptive transfer of CD103+ CD8 T cells promotes tumor growth, whereas CD103 blockade limits tumorigenesis. Thus, anti-LAP targets multiple immunoregulatory pathways and represents a potential approach for cancer immunotherapy.
Author Info: (1) Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (2) Ann Romn
Author Info: (1) Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (2) Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA. (3) Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (4) Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (5) Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (6) Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (7) Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (8) Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (9) Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (10) Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (11) Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (12) Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (13) Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte 31.270-901, Brazil. (14) Department of Biochemistry and Immunology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte 31.270-901, Brazil. (15) Center for Brain Research, Medical University of Vienna, Spitalgasse 4, A-1090 Wien, Austria. (16) Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (17) Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (18) Ann Romney Center for Neurologic Diseases, Evergrande Center for Immunologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. hweiner@rics.bwh.harvard.edu.
