Editors' ChoiceCancer

Blocking cell death to enhance cell death

See allHide authors and affiliations

Science Translational Medicine  20 Sep 2017:
Vol. 9, Issue 408, eaao6129
DOI: 10.1126/scitranslmed.aao6129


Inhibiting caspase activation during apoptosis may enhance the ability of the immune system to target cancer cells.

To achieve optimal responses to cancer therapy, one must potently induce cell death in cancer cells. Most anticancer therapies—including cytotoxic and targeted chemotherapies, as well as ionizing radiation—engage the apoptosis pathway to eradicate cancer cells. Apoptosis is responsible for the efficient removal of billions of our cells each day and has thus been engineered by evolution to be immunologically silent so that rampant inflammation is not triggered by each dying cell. When apoptosis is triggered by activation of the mitochondrial membrane pore-forming proteins BAX or BAK and consequent release of cytochrome c from mitochondria, the cell is irreversibly committed to death. Caspases 3 and 7 are activated during this process to ensure the orderly dismantling of the cell and preparation for engulfment by macrophages. As a potential improvement upon this paradigm in cancer therapy, Giampazolias and colleagues reasoned that if they allowed cancer cells to engage the apoptosis pathway and undergo cytochrome c release, but blocked the activation of caspases, the cells would not be efficiently cleared, and thus the dying cells could stimulate an immune response toward any remaining cancer cells that are alive.

Using several in vivo models, the group demonstrated that blocking caspase activation in cancer cells undergoing apoptosis supported stronger activation of the immune system than cells that could activate caspases. As they had reasoned, blocking caspases enhanced immune-mediated tumor control and drove more complete remissions. Careful mechanistic studies demonstrated that this effect is dependent on activation of the proinflammatory nuclear factor κB pathway via release of key proteins during mitochondrial permeabilization. Interestingly, the authors also observed that syngeneic tumors in immune competent mice grew more slowly when caspases were inhibited than those with efficient clearance of dead cells. This suggests that cancer cells that are naturally shed via caspase-independent cell death during normal tumor growth in vivo may be activating an antitumor immune response, resulting in reduced tumor growth. Overall, these exciting studies suggest that blocking caspases in cancer cells during treatment with chemotherapy or radiation could potentially greatly enhance antitumor immune responses. Although major questions remain, such as whether this strategy has relevance to the many tumor types that are refractory to therapy in general and whether this can actually improve patient responses in the clinic, these exciting findings should stimulate additional, much-needed research in this field.

Highlighted Article

Stay Connected to Science Translational Medicine

Navigate This Article