Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice.
Level 5 - mechanism / opinion, no new human data
Preclinical animal and bench research
PubMed 22174255 · doi:10.1126/science.1208347
What was done
Researchers evaluated whether tumor autophagy is required for chemotherapy-induced immunogenic cell death and antitumor immune responses in mice. They compared immune cell infiltration (dendritic cells and T lymphocytes) into the tumor bed, measured extracellular adenosine triphosphate (ATP) release in autophagy-competent versus autophagy-deficient tumor models, and tested the effects of inhibiting extracellular ATP-degrading enzymes in immunocompetent hosts.
What was found
No quantitative data were reported in the abstract. Autophagy was dispensable for chemotherapy-induced cell death but required for its immunogenicity. In response to chemotherapy, autophagy-competent tumors recruited dendritic cells and T lymphocytes into the tumor bed, whereas autophagy-deficient tumors did not. Autophagy suppression blocked ATP release from dying tumor cells. Inhibiting extracellular ATP-degrading enzymes increased pericellular ATP, restored immune cell recruitment, and reestablished chemotherapeutic efficacy in autophagy-deficient tumors in immunocompetent hosts.
Why it matters
This study identifies autophagy-dependent ATP release as a critical mechanism connecting antineoplastic chemotherapy to adaptive antitumor immune responses. It suggests that increasing extracellular ATP concentrations may overcome impaired chemotherapy responses in autophagy-deficient cancers.
Limits
The study is entirely preclinical in animal and cell models with no human clinical validation. The abstract reports no numerical data, confidence intervals, sample sizes, tumor types, or specific chemotherapeutic regimens tested.
Cited by
- supports Autophagy is required for stressed cancer cells to release extracellular ATP as a danger signal that attracts myeloid cells via purinergic receptors to initiate an anti-cancer immune response.
- partial Long-term clinical efficacy of chemotherapy depends on inducing cancer cell death that elicits an anti-cancer immune response via autophagy induction.
- supports Combining caloric restriction mimetics like spermidine, hydroxycitrate, or resveratrol with chemotherapy enhances the anti-cancer immune response, and this benefit is lost if malignant cell autophagy is inhibited, extracellular ATP is destroyed, or T cells are removed.