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TLR4 is essential for dendritic cell activation and anti-tumor T-cell response enhancement by DAMPs released from chemically stressed cancer cells

Cellular & Molecular Immunology volume 11, pages 150–159 (2014)Cite this article

Abstract

The combination of immunotherapy and chemotherapy is regarded as a promising approach for the treatment of certain types of cancer. However, the underlying mechanisms need to be fully investigated to guide the design of more efficient protocols for cancer chemoimmunotherapy. It is well known that danger-associated molecular patterns (DAMPs) can activate immune cells, including dendritic cells (DCs), via Toll-like receptors (TLRs); however, the role of DAMPs released from chemical drug-treated tumor cells in the activation of the immune response needs to be further elucidated. Here, we found that colorectal cancer (CRC) cells treated with oxaliplatin (OXA) and/or 5-fluorouracil (5-Fu) released high levels of high-mobility group box 1 (HMGB1) and heat shock protein 70 (HSP70). After OXA/5-Fu therapy, the sera of CRC patients also exhibited increased levels of HMGB1 and HSP70, both of which are well-known DAMPs. The supernatants of dying CRC cells treated with OXA/5-Fu promoted mouse and human DC maturation, with upregulation of HLA-DR, CD80 and CD86 expression and enhancement of IL-1β, TNF-α, MIP-1α, MIP-1β, RANTES and IP-10 production. Vaccines composed of DCs pulsed with the supernatants of chemically stressed CRC cells induced a more significant IFN-γ-producing Th1 response both in vitro and in vivo. However, the supernatants of chemically stressed CRC cells failed to induce phenotypic maturation and cytokine production in TLR4-deficient DCs, indicating an essential role of TLR4 in DAMP-induced DC maturation and activation. Furthermore, pulsing with the supernatants of chemically stressed CRC cells did not efficiently induce an IFN-γ-producing Th1 response in TLR4-deficient DCs. Collectively, these results demonstrate that DAMPs released from chemically stressed cancer cells can activate DCs via TLR4 and enhance the induction of an anti-tumor T-cell immune response, delineating a clinically relevant immuno-adjuvant pathway triggered by DAMPs.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (81273332, 81101657 and 81123006) and the National High Technology Research, Development Program of China (2012AA020902).

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  1. Hongliang Fang and Bing Ang: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, 310058, China

    Hongliang Fang & Xuetao Cao

  2. National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai, 200433, China

    Bing Ang, Xiaohui Huang, Yanfeng Wu, Wenying Wang, Nan Li, Xuetao Cao & Tao Wan

  3. Department of General Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China

    Xinyun Xu & Yanping Sun

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Fang, H., Ang, B., Xu, X. et al. TLR4 is essential for dendritic cell activation and anti-tumor T-cell response enhancement by DAMPs released from chemically stressed cancer cells. Cell Mol Immunol 11, 150–159 (2014). https://doi.org/10.1038/cmi.2013.59

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