Targeting latency-associated peptide promotes antitumor immunity

Abstract

Regulatory T cells (T_regs) promote cancer by suppressing antitumor immune responses. We found that anti-LAP antibody, which targets the latency-associated peptide (LAP)/transforming growth factor-β (TGF-β) complex on T_regs and other cells, enhances antitumor immune responses and reduces tumor growth in models of melanoma, colorectal carcinoma, and glioblastoma. Anti-LAP decreases LAP⁺ T_regs, tolerogenic dendritic cells, and TGF-β 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-γ, tumor necrosis factor-α, 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.