Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy

Nat Med.13:1050-1059, 2007

Speaker: 林怡璇                          Date: 2007/09/26 13:10~14:00

Commentator: 楊倍昌 老師                Place: Room 601

Abstract:

    Radiotherapy and chemotherapy are main methods in the conventional cancer therapy, and it is believed that the prime goal of therapy is to directly eliminate of tumor cells. Although apoptosis may be a silent cell death modality^[1], some types of tumor cell death can also induce antitumor immune responses depending on the cell death inducer. It is generally assumed that cell death can elicit an immune response only if dying cells emit ‘eat me’ and ‘danger’ signals that mediate their efficient phagocytosis by dendritic cells (DCs) and the maturation of DCs, respectively^[2]. However, endogenous ‘danger’ signals have thus far not been implicated in antitumor immune response. In this study, the authors used Toll like receptor (TLR)^-/- DC or transgenic mice to determine which TLR might control the immune response against dying tumor cells. TLR4 is a cell surface receptor of several damage-associated molecular patterns and may control the processing and presentation of peptides derived from internalized cargo. They demonstrated that both the release of high-mobility-group box 1 (HMGB1) by dying tumor cells and the TLR4 and its adaptor myeloid differentiation primary response protein-88 (MyD88) signaling pathway in DCs are required for the efficient processing and cross-presentation of antigens from dying tumor cells against dying tumor cells and also for the efficacy of anticancer chemotherapy and radiotherapy in mice. Patients with breast cancer who carry a TLR4 loss-of-function allele relapse more quickly after radiotherapy and chemotherapy than those carrying the normal TLR4 allele. Here, the authors found that dying tumor cells produced by cancer therapies trigger a cognate immune response in a TLR4-dependent fashion.

References:

1.          Winau, F. et al. (2006) Apoptotic vesicles crossprime CD8 T cells and protect against tuberculosis. Immunity 24, 105-117

2.          Casares, N. et al. (2005) Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J. Exp. Med. 202, 1691-1701