A Better Way for a Cancer Cell to Die
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《新英格兰医药杂志》
In their recent study of the lethal effects of chemotherapy on cancer cells, Casares et al.1 have shown that, after the fatal blow, cancer cells can take different pathways to death's door, depending on the chemotherapeutic agent used. One of these routes has immunologic consequences with important clinical implications; the other kills the cell without exciting the immune system.1 The experiments, carried out in mice carrying subcutaneous tumors, indicate that if a chemotherapeutic agent kills cancer cells in a way that renders them immunogenic, it has a therapeutic benefit over and above the cytotoxic action of the drug. The study also reinforces the notion that the interaction of dead and dying cells with the immune system can be positive, neutral, or negative.2
How does the way a cell dies make a difference to the immune system? The primary mode of action of different chemotherapeutic drugs varies widely, but the end result is often the same: the initiation of a biochemical cascade (programmed cell death) that culminates in a form of cell death called apoptosis. Important mediators of apoptosis are the asparate-specific cysteine proteases, or caspases, especially caspase 3.
Every day, billions of normal cells in the body undergo apoptosis; if just a fraction of them were immunogenic, autoimmunity would be a serious problem. Since autoimmunity is not common, this form of apoptosis has been considered nonimmunogenic, or bland. In contrast to bland apoptosis, cell death in the presence of proinflammatory microbial products — such as lipopolysaccharide, unmethylated cytidine–phosphate–guanosine motifs, and double-stranded RNA — triggers a protective immune response. A tumor cell killed by chemotherapy is thought to lack proinflammatory molecules and should therefore elude notice by the immune system. The actual situation, however, is more complex. Apoptotic tumor cells, but not malignant cells in necrotic tumors, can provoke an antitumor immune response.3 Now, Casares et al. refine our knowledge of the situation by showing that not all forms of apoptosis are equal with respect to the immune system. Two drugs — doxorubicin and mitomycin — that bind to DNA and induce apoptosis in tumor cells were used, but the apoptotic cells that were killed by doxorubicin triggered an immune reaction, whereas the apoptotic cells killed by mitomycin did not.
The investigators showed in a mouse model that colon-carcinoma cells (CT26 cell line) that were killed by doxorubicin (an agent that intercalates with DNA) were first taken up by dendritic cells and then induced the proliferation of antitumor cytotoxic CD8+ T cells (Figure 1). These apoptotic cells — killed by doxorubicin — inhibited the growth of small tumors. Furthermore, established CT26 cancer cells regressed after doxorubicin was injected directly into the tumor. These events occurred only when the tumor cells were killed in a caspase 3–dependent manner, which stresses the importance of apoptosis. By contrast, dendritic cells ignored CT26 cells in which apoptosis was induced by mitomycin, and there was no immune response against the cells. The treatment of these mitomycin-killed cells with doxorubicin (which would be expected to be intercalated with the DNA of the newly killed cells) failed to make the cells immunogenic, indicating that the induction of apoptosis by doxorubicin was critical to the outcome.
Figure 1. Harnessing the Immune System to Kill Cancer Cells.
Cancer cells that die after treatment with cytotoxic agents can be processed by dendritic cells for presentation to CD4+CD8+ T cells. Some drugs initiate a program of targeting and killing cells that amplifies this process. Dying cells then express molecules that serve as danger signals (yellow box) that activate dendritic cells to present cancer antigens in an inflammatory context. In response, dendritic cells up-regulate costimulatory molecules and secrete cytokines such as interleukin-12. Immunotherapies that target dendritic cells (blue box) may induce an effective immune response even if danger signals are not expressed by dying tumor cells. Additional immunotherapies directed at T cells (red box) may also promote antitumor immunity.
This study raises two important questions. What are the immunogenic markers of a dead cell? And how can these new insights be applied in clinical settings? In our view, these questions are related. Once we know how the immune system decodes cell death, we can design therapies that exploit that mechanism (Figure 1). From a clinical point of view, the most readily translatable finding from the study is that intratumoral injection of doxorubicin, but not mitomycin, led to a complete regression of cancer in some immunocompetent mice. Current experience suggests, however, that intratumoral injection of doxorubicin would probably not ablate cancers in humans. In the treatment of mesothelioma, the procedure is associated with considerable morbidity and has a limited survival benefit.4 It is possible, however, that the immunogenicity of tumor cells killed by doxorubicin has gone unnoticed because the response is too weak to affect the tumor. If this turns out to be the case, the boosting of T-cell responses with cytokines or vaccines (once developed) may be an option.
The application of the finding that doxorubicin mediates the immunogenic death of a tumor cell faces two additional obstacles. First, not all tumors are sensitive to doxorubicin, and second, doxorubicin is often used in combination with other chemotherapies that could affect immunogenicity — as is shown by Casares et al. Clearly, further investigation of the immunogenic potential of other chemotherapeutic drugs, both alone and in combination, is warranted. When the administration of chemotherapy results in only weakly immunogenic dead tumor cells, targeted immunotherapy may be an alternative. In fact, immunotherapies aimed at the immune system itself (Figure 1) may be more versatile if they can be used with any chemotherapy, so that for a particular cancer, a clinical trial would test a supplementary protocol added to the current best practice.
No potential conflict of interest relevant to this article was reported.
Source Information
From the University of Western Australia, Perth.
References
Casares N, Pequignot MO, Tesniere A, et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J Exp Med 2005;202:1691-1701.
Lake RA, Robinson BW. Immunotherapy and chemotherapy -- a practical partnership. Nat Rev Cancer 2005;5:397-405.
Scheffer SR, Nave H, Korangy F, et al. Apoptotic, but not necrotic, tumor cell vaccines induce a potent immune response in vivo. Int J Cancer 2003;103:205-211.
van Ruth S, Baas P, Haas RL, Rutgers EJ, Verwaal VJ, Zoetmulder FA. Cytoreductive surgery combined with intraoperative hyperthermic intrathoracic chemotherapy for stage I malignant pleural mesothelioma. Ann Surg Oncol 2003;10:176-182.(Richard A. Lake, Ph.D., a)
How does the way a cell dies make a difference to the immune system? The primary mode of action of different chemotherapeutic drugs varies widely, but the end result is often the same: the initiation of a biochemical cascade (programmed cell death) that culminates in a form of cell death called apoptosis. Important mediators of apoptosis are the asparate-specific cysteine proteases, or caspases, especially caspase 3.
Every day, billions of normal cells in the body undergo apoptosis; if just a fraction of them were immunogenic, autoimmunity would be a serious problem. Since autoimmunity is not common, this form of apoptosis has been considered nonimmunogenic, or bland. In contrast to bland apoptosis, cell death in the presence of proinflammatory microbial products — such as lipopolysaccharide, unmethylated cytidine–phosphate–guanosine motifs, and double-stranded RNA — triggers a protective immune response. A tumor cell killed by chemotherapy is thought to lack proinflammatory molecules and should therefore elude notice by the immune system. The actual situation, however, is more complex. Apoptotic tumor cells, but not malignant cells in necrotic tumors, can provoke an antitumor immune response.3 Now, Casares et al. refine our knowledge of the situation by showing that not all forms of apoptosis are equal with respect to the immune system. Two drugs — doxorubicin and mitomycin — that bind to DNA and induce apoptosis in tumor cells were used, but the apoptotic cells that were killed by doxorubicin triggered an immune reaction, whereas the apoptotic cells killed by mitomycin did not.
The investigators showed in a mouse model that colon-carcinoma cells (CT26 cell line) that were killed by doxorubicin (an agent that intercalates with DNA) were first taken up by dendritic cells and then induced the proliferation of antitumor cytotoxic CD8+ T cells (Figure 1). These apoptotic cells — killed by doxorubicin — inhibited the growth of small tumors. Furthermore, established CT26 cancer cells regressed after doxorubicin was injected directly into the tumor. These events occurred only when the tumor cells were killed in a caspase 3–dependent manner, which stresses the importance of apoptosis. By contrast, dendritic cells ignored CT26 cells in which apoptosis was induced by mitomycin, and there was no immune response against the cells. The treatment of these mitomycin-killed cells with doxorubicin (which would be expected to be intercalated with the DNA of the newly killed cells) failed to make the cells immunogenic, indicating that the induction of apoptosis by doxorubicin was critical to the outcome.
Figure 1. Harnessing the Immune System to Kill Cancer Cells.
Cancer cells that die after treatment with cytotoxic agents can be processed by dendritic cells for presentation to CD4+CD8+ T cells. Some drugs initiate a program of targeting and killing cells that amplifies this process. Dying cells then express molecules that serve as danger signals (yellow box) that activate dendritic cells to present cancer antigens in an inflammatory context. In response, dendritic cells up-regulate costimulatory molecules and secrete cytokines such as interleukin-12. Immunotherapies that target dendritic cells (blue box) may induce an effective immune response even if danger signals are not expressed by dying tumor cells. Additional immunotherapies directed at T cells (red box) may also promote antitumor immunity.
This study raises two important questions. What are the immunogenic markers of a dead cell? And how can these new insights be applied in clinical settings? In our view, these questions are related. Once we know how the immune system decodes cell death, we can design therapies that exploit that mechanism (Figure 1). From a clinical point of view, the most readily translatable finding from the study is that intratumoral injection of doxorubicin, but not mitomycin, led to a complete regression of cancer in some immunocompetent mice. Current experience suggests, however, that intratumoral injection of doxorubicin would probably not ablate cancers in humans. In the treatment of mesothelioma, the procedure is associated with considerable morbidity and has a limited survival benefit.4 It is possible, however, that the immunogenicity of tumor cells killed by doxorubicin has gone unnoticed because the response is too weak to affect the tumor. If this turns out to be the case, the boosting of T-cell responses with cytokines or vaccines (once developed) may be an option.
The application of the finding that doxorubicin mediates the immunogenic death of a tumor cell faces two additional obstacles. First, not all tumors are sensitive to doxorubicin, and second, doxorubicin is often used in combination with other chemotherapies that could affect immunogenicity — as is shown by Casares et al. Clearly, further investigation of the immunogenic potential of other chemotherapeutic drugs, both alone and in combination, is warranted. When the administration of chemotherapy results in only weakly immunogenic dead tumor cells, targeted immunotherapy may be an alternative. In fact, immunotherapies aimed at the immune system itself (Figure 1) may be more versatile if they can be used with any chemotherapy, so that for a particular cancer, a clinical trial would test a supplementary protocol added to the current best practice.
No potential conflict of interest relevant to this article was reported.
Source Information
From the University of Western Australia, Perth.
References
Casares N, Pequignot MO, Tesniere A, et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J Exp Med 2005;202:1691-1701.
Lake RA, Robinson BW. Immunotherapy and chemotherapy -- a practical partnership. Nat Rev Cancer 2005;5:397-405.
Scheffer SR, Nave H, Korangy F, et al. Apoptotic, but not necrotic, tumor cell vaccines induce a potent immune response in vivo. Int J Cancer 2003;103:205-211.
van Ruth S, Baas P, Haas RL, Rutgers EJ, Verwaal VJ, Zoetmulder FA. Cytoreductive surgery combined with intraoperative hyperthermic intrathoracic chemotherapy for stage I malignant pleural mesothelioma. Ann Surg Oncol 2003;10:176-182.(Richard A. Lake, Ph.D., a)