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Molecular Interactions between Dying Tumor Cells and the Innate Immune System Determine the Efficacy of Conventional Anticancer Therapies

¹ Institut National de la Sante et de la Recherche Medicale, U805, ² Institut Gustave Roussy, ³ Institut National de la Sante et de la Recherche Medicale, U848, and ⁴ CIC BT507,Villejuif, France; ⁵ Université Paris XI, Le Kremlin Bicêtre, France; and ⁶ Département d'oncologie médicale, Centre Georges-François Leclerc, and ⁷ CRI Institut National de la Sante et de la Recherche Medicale 866 Faculté de Médecine, Dijon, France

Requests for reprints: Laurence Zitvogel, Institut National de la Sante et de la Recherche Medicale, U805, Institut Gustave Roussy, 39 rue Camille Desmoulins, F-94805 Villejuif, France. Phone: 33-1-42-11-50-41; Fax: 33-1-42-11-60-94; E-mail: zitvogel{at}igr.fr or Guido Kroemer, Institut National de la Sante et de la Recherche Medicale, U848. Phone: 33-1-42-11-60-46; Fax: 33-1-42-11-60-47; E-mail: kroemer{at}igr.fr.

Key Words: TLR4 • HMGB1 • dendritic cell • chemotherapy

The efficacy of anticancer treatments is mostly assessed by their ability to directly inhibit the proliferation of tumor cells. Recently, we showed that tumor cell death triggered by chemotherapy or radiotherapy initiates an immunoadjuvant pathway that contributes to the success of cytotoxic treatments. The interaction of high mobility group box 1 protein (HMGB1) released from dying tumor cells with Toll-like receptor 4 (TLR4) on dendritic cells was required for the crosspresentation of tumor antigens and the promotion of tumor specific cytotoxic T-cell responses. Breast cancer patients harboring the loss-of-function Asp299Gly polymorphism of TLR4 relapsed earlier after receiving anthracycline-based chemotherapy. These data suggests that HMGB1- and TLR4-dependent immune responses elicited by conventional cancer treatment may increase the probability to achieve a durable therapeutic success. [Cancer Res 2008;68(11):4026–30]

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