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Toll-Like Receptors on Tumor Cells Facilitate Evasion of Immune Surveillance

Departments of ¹ Gene and Cell Medicine and ² Biochemistry and Pharmacology, ³ Immunobiology Center, Mount Sinai School of Medicine; ⁴ Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, New York; and ⁵ Department of Immunology, Shanghai Medical College, Fudan University, Shanghai

Requests for reprints: Huabao Xiong, Immunobiology Center, Box 1630, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029-6574. Phone: 212-659-9413; Fax: 212-849-2525; E-mail: Huabao.Xiong{at}mssm.edu.

The signal pathways that trigger tumor cell escape from immune surveillance are incompletely understood. Toll-like receptors (TLRs), which activate innate and adaptive immune responses, are thought to be restricted to immune cells. We show here that TLRs, including TLR4, are expressed on tumor cells from a wide variety of tissues, suggesting that TLR activation may be an important event in tumor cell immune evasion. Activation of TLR4 signaling in tumor cells by lipopolysaccharide induces the synthesis of various soluble factors and proteins including interleukin-6, inducible nitric oxide synthase, interleukin-12, B7-H1, and B7-H2, and results in resistance of tumor cells to CTL attack. In addition, lipopolysaccharide-stimulated tumor cell supernatants inhibit both T cell proliferation and natural killer cell activity. Blockade of the TLR4 pathway by either TLR4 short interfering RNA or a cell-permeable TLR4 inhibitory peptide reverses tumor-mediated suppression of T cell proliferation and natural killer cell activity in vitro, and in vivo, delays tumor growth and thus prolongs the survival of tumor-bearing mice. These findings indicate that TLR signaling results in a cascade leading to tumor evasion from immune surveillance. These novel functions of TLRs in tumor biology suggest a new class of therapeutic targets for cancer therapy.

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