A Better Way for a Cancer Cell to Die
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n engl j med 354;23 www.nejm.org june 8, 2006 2503 clinical implications of basic research The new england journal of medicine A Better Way for a Cancer Cell to Die Richard A. Lake, Ph.D., and Robbert G. van der Most, Ph.D. In their recent study of the lethal effects of chemo- therapy 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 im- portant clinical implications; the other kills the cell without exciting the immune system. 1 The experiments, carried out in mice carrying subcu- taneous tumors, indicate that if a chemotherapeu- tic 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 in- teraction 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 ac- tion 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 apopto- sis 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 non- immunogenic, or bland. In contrast to bland apoptosis, cell death in the presence of proin- flammatory microbial products — such as lipo- polysaccharide, unmethylated cytidine–phos- phate–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 im- mune 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 ap- optotic cells that were killed by doxorubicin trig- gered 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 inter- calates with DNA) were first taken up by den- dritic cells and then induced the proliferation of antitumor cytotoxic CD8+ T cells (Fig. 1). These apoptotic cells — killed by doxorubicin — in- hibited 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, in- dicating that the induction of apoptosis by doxo- rubicin was critical to the outcome. 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 (Fig. 1). From a clinical point of view, the most readily translatable find- ing from the study is that intratumoral injection of doxorubicin, but not mitomycin, led to a com- plete regression of cancer in some immunocom- petent mice. Current experience suggests, how- ever, that intratumoral injection of doxorubicin would probably not ablate cancers in humans. In the treatment of mesothelioma, the procedure is The New England Journal of Medicine Downloaded from nejm.org at UNIV OF SO DAKOTA on April 29, 2013. For personal use only. No other uses without permission. Copyright © 2006 Massachusetts Medical Society. All rights reserved.
Transcript of A Better Way for a Cancer Cell to Die
n engl j med 354;23 www.nejm.org june 8, 2006 2503
clinical implications of basic research
T h e n e w e ng l a nd j o u r na l o f m e dic i n e
A Better Way for a Cancer Cell to DieRichard A. Lake, Ph.D., and Robbert G. van der Most, Ph.D.
In their recent study of the lethal effects of chemo-therapy 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 im-portant clinical implications; the other kills the cell without exciting the immune system.1 The experiments, carried out in mice carrying subcu-taneous tumors, indicate that if a chemotherapeu-tic 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 in-teraction 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 ac-tion 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 apopto-sis 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 non-immunogenic, or bland. In contrast to bland apoptosis, cell death in the presence of proin-flammatory microbial products — such as lipo-polysaccharide, unmethylated cytidine–phos-phate–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 im-mune 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 ap-optotic cells that were killed by doxorubicin trig-gered 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 inter-calates with DNA) were first taken up by den-dritic cells and then induced the proliferation of antitumor cytotoxic CD8+ T cells (Fig. 1). These apoptotic cells — killed by doxorubicin — in-hibited 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, in-dicating that the induction of apoptosis by doxo-rubicin was critical to the outcome.
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 (Fig. 1). From a clinical point of view, the most readily translatable find-ing from the study is that intratumoral injection of doxorubicin, but not mitomycin, led to a com-plete regression of cancer in some immunocom-petent mice. Current experience suggests, how-ever, that intratumoral injection of doxorubicin would probably not ablate cancers in humans. In the treatment of mesothelioma, the procedure is
The New England Journal of Medicine Downloaded from nejm.org at UNIV OF SO DAKOTA on April 29, 2013. For personal use only. No other uses without permission.
Copyright © 2006 Massachusetts Medical Society. All rights reserved.
n engl j med 354;23 www.nejm.org june 8, 20062504
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 re-sponse 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 devel-oped) may be an option.
The application of the finding that doxorubi-cin 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 immuno-genicity — as is shown by Casares et al. Clearly, further investigation of the immunogenic poten-tial of other chemotherapeutic drugs, both alone and in combination, is warranted. When the ad-ministration 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 (Fig. 1) may be more versatile if they can be used with any chemotherapy, so that for a particu-lar cancer, a clinical trial would test a supplemen-tary protocol added to the current best practice.
No potential conflict of interest relevant to this article was re-ported.
From the University of Western Australia, Perth.
Casares N, Pequignot MO, Tesniere A, et al. Caspase-depen-dent immunogenicity of doxorubicin-induced tumor cell death. J Exp Med 2005;202:1691-701.
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;103:205-11.
van Ruth S, Baas P, Haas RL, Rutgers EJ, Verwaal VJ, Zoet-mulder FA. Cytoreductive surgery combined with intraoperative hyperthermic intrathoracic chemotherapy for stage I malignant pleural mesothelioma. Ann Surg Oncol 2003;10:176-82.Copyright © 2006 Massachusetts Medical Society.
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Tumor mass
Growth inhibitionTumor regression
Tumor cell
Dying tumor cellProcessing of
tumor antigens
Uric acid
Presentation oftumor antigens
Dead tumor cell
Dendritic cellPhagocytosisChemotherapy
ActivatedCD4+CD8+ T cells
Toll-like receptor ligandsAnti-CD40 therapyInterleukin-12
RAE1Uric acid
Cytokines (interleukin-2and interleukin-21)Vaccines
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 im-mune 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.
Clinical Implications of Basic Research
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