Research ArticleCANCER IMMUNOLOGY

Targeting latency-associated peptide promotes antitumor immunity

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Science Immunology  19 May 2017:
Vol. 2, Issue 11, eaaj1738
DOI: 10.1126/sciimmunol.aaj1738

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LAPping up tumor immunoregulation

Tumors dodge the immune system in part by promoting immune regulatory cells. Gabriely et al. now report that antibodies to latency-associated peptide (LAP), which forms a complex with transforming growth factor–β (TGF-β), reduced tumor growth in multiple cancer models in mice. The authors found that antibodies to LAP decreased numbers of LAP+ regulatory T cells and tolerogenic dendritic cells within the tumor and TGF-β secretion in vitro. Moreover, anti-LAP antibodies decreased numbers of CD103+ CD8+ T cells in lymphoid organs; these cells were then shown to promote tumor growth. Furthermore, combining LAP antibodies with antigen-specific vaccination enhanced both antitumor immune response and immunological memory. Together, these data suggest that targeting LAP may enhance tumor immunotherapy.

Abstract

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–β (TGF-β) 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-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.

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