Major finding: Autophagy defects suppress chemotherapy-induced immunogenic signaling in tumors.
Concept: Extracellular ATP released by autophagic cells recruits dendritic cells and T lymphocytes.
Impact: Restoring local ATP concentrations may enhance tumor immunogenicity and drug sensitivity.
The efficiency of some cytotoxic chemotherapeutic agents depends on the ability of dying tumor cells to stimulate an immune response. Key features of immunogenic cell death include preapoptotic cell surface exposure of calreticulin (CRT), postapoptotic high-mobility group protein B1 (HMGB1) release, and ATP secretion. CRT, HMGB1, and ATP all interact with dendritic cell (DC) surface receptors to stimulate a multifaceted antitumor immune response. The cellular processes that result in CRT exposure and HMGB1 release are well characterized, but the mechanism underlying chemotherapy-induced ATP secretion is unknown. Michaud and colleagues hypothesized that autophagy, a cell death mechanism with links to both stress and immune responses, may contribute to immunogenic signaling in response to chemotherapy. Autophagic components were knocked down in mitoxantrone (MTX)- or oxaliplatin-treated murine colorectal carcinoma cells, and the supernatants were analyzed for markers of immunogenic cell death. Autophagy-deficient tumor cells exposed CRT, released HMGB1, and underwent apoptosis in response to chemotherapy but secreted less ATP when treated with MTX or oxaliplatin than did the autophagy-competent cells. Impairment of autophagy in MTX-treated cells also prevented the dying cells from eliciting a protective anticancer immune response when they were injected into syngeneic, immunocompetent mice, due to the failure to recruit DCs and lymphocytes. Artificial enhancement of extracellular ATP concentrations by intratumoral injection of an ecto-ATPase (apyrase) inhibitor restored both the immunogenicity of MTX-treated, autophagy-deficient cells and the efficacy of MTX and oxaliplatin against autophagy-deficient tumors. Because autophagic cell death is often disabled in malignant cells, these findings suggest that enhancement of pericellular ATP within tumors may compensate for defective immunogenic signaling and improve chemotherapeutic responses.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at www.AACR.org/CDnews.
