[Immunological aspects of anticancer chemotherapy].
For over 40 years, four therapeutic modalities, namely surgery, radiotherapy, chemotherapy and hormone therapy have formed the core of anticancer treatments. Their mode of action is thought to involve a direct cytotoxic action on tumor cells. Recently, the discovery of tumor-associated immunosuppression and tumor immunosurveillance has led to cancer being reconsidered not only as an organ disease but also as a host disease. This new concept is supported by the recent discovery of the immunogenic effects of tumor cell death induced by a variety of cytotoxic drugs. This work describes a new pathway of tumor-derived antigen presentation mediated by the alarmin HMGB1 (released by dying tumor cells in response to chemo/radiotherapy) and by TLR4 on dendritic cells. In this model, TLR4 recognizes? tumor-derived antigens, leading to T cell activation and to the induction of an antitumor immune response. Accordingly, we show that breast cancer patients bearing a loss-of-function mutation of the TLR4 receptor have shorter disease-free survival, confirming the major role of the immune system in the response to cytotoxic treatments. The response to chemotherapy and/or radiotherapy may thus combine both direct cytotoxic effects and the development of long-term antitumor immunity. We anticipate that these new results will have major impact on cancer management.
Zitvogel
Laurence
L
Institut Gustave Roussy, F-94805 Villejuif, 39, rue Camille Desmoulins, France.
Tesniere
Antoine
A
Apetoh
Lionel
L
Ghiringhelli
François
F
Kroemer
Guido
G
D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000532:radiotherapy / Q000601:surgery; D045744:Cell Line, Tumor / Q000187:drug effects / Q000276:immunology; D003131:Combined Modality Therapy; D003713:Dendritic Cells / Q000276:immunology; D018572:Disease-Free Survival; D024243:HMGB1 Protein / Q000235:genetics / Q000502:physiology*; D006367:HeLa Cells / Q000276:immunology; D006801:Humans; D007157:Immunologic Surveillance / Q000187:drug effects; D008545:Melanoma / Q000473:pathology; D018448:Models, Immunological; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology; D020641:Polymorphism, Single Nucleotide; D011878:Radiotherapy / Q000009:adverse effects; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012189:Retrospective Studies; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000502:physiology*
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D024243:HMGB1 Protein; D011993:Recombinant Fusion Proteins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4