Molecular basis of the immunogenicity of cell death during chemotherapy

SY29-04 Conventional therapies of cancer rely upon cytotoxic agents such as radio- and chemotherapy. Such treatments supposedly mediate their effects via the direct elimination of tumor cells. We reported that anthracyclin, X-Rays and platinum based-therapies mediate optimal antitumor efficacy against established mouse tumors in immunocompetent but not immunocomprised littermates. Dying tumor cells or locally irradiated tumor beds prime naive T cells in their draining lymph nodes and induce Th1 differentiation. This finding paved the way to the demonstration that dendritic cells (DC) are pivotal in the immunogenicity of cell death triggered by anticancer drugs.
 First, phagocytosis of dying tumor cells by DC requires translocation of calreticulin to the tumor cell surface (Obeid et al. Nat. Med. Jan. 2007).
 Second, dying tumor cells release high mobility group box 1 protein from their nuclei which will trigger TLR4 receptors harboured on DC. TLR4 signaling is indeed mandatory for the immunogenicity of cell death to promote the efficient processing of tumor cells by DC (Apetoh et al. Nat. Med. Aug. 2007). TLR4 deficient mice failed to respond to X-Rays or anthracyclins or oxaliplatinum. However, cotreatment with TLR9 or TLR3 agonists or with chloroquine (a drug regulating lysosomal pH) could compensate for the TLR4 defects in antigen processing and presentation (Apetoh, Immunol; Rev. 2007).
 We recently delineated additional molecular pathways critical for the polarization of the T cell immune responses that will be further discussed at the meeting.
 The clinical relevance of these preclinical findings has been evaluated in patients receiving anticancer chemotherapy. The TLR4 status could predict the therapeutic outcome in breast cancer females treated with systemic anthracyclins. Patients carrying a TLR4 loss-of-function allele (Asp299Gly) manifested a higher incidence of metastases at ten years (50% versus 37.4% in non mutated patients) after surgery (Log rank test, p = 0.03). Similar trends were found in colon cancer patients treated with 5FU and/or oxaliplatinum-based regimen. These results delineate a clinically relevant immunoadjuvant pathway triggered by tumor cell death that could be exploited to ameliorate the efficacy of current therapies in defined cohorts of patients.