Immunogenicity of Cytotoxic Drugs: Molecular Bases and Clinical Implementation

PL05-04 Conventional cancer management still relies on the four modalities experienced since 40 years ie surgery, radiotherapy, cytotoxic chemotherapy and hormonotherapy. Most of these therapies are believed to directly attack or eradicate the tumor burden. The emerging concept that cancer is not just a disease of a tissue or an organ but also a host disease is relying on emerging evidence of tumor-induced immunosuppression and polymorphism in genes involved in host protection against tumors. This theory is now fueled by our recent data showing that the immunoadjuvant effects of tumor cell death generated by cytotoxic anticancer agents are required for the antitumor efficacy. First we demonstrated that upon exposure to anthracyclins or X-Rays, tumor cells translocate the calreticulin (CRT) from the endoplasmic pool to the cell surface, a signal mandatory for dendritic cells to uptake dying tumor cells. The ecto-CRT exposure is mandatory for the immunogenicity of cell death induced by chemotherapy and long term survival in mice (Obeid et al, Nat. Med. Jan. 2007). Second, we showed that the release of the high mobility group box 1 protein (HMGB1) by dying tumor cells is mandatory to license host dendritic cells (DC) to process tumor antigens. HMGB1 interact with TLR4 receptors on DC which are selectively involved in the cross-priming of antitumor-T lymphocytes in vivo (Apetoh et al. Nat.Med. Aug. 2007). A TLR4 polymorphism (Asp299Gly) affecting the binding of HMGB1 to the receptor can predict an earlier relapse after anthracycline-based chemotherapy in breast cancer patients. This knowledge may be clinically exploited to enhance the immunogenicity of current chemotherapeutic regimens.