Purpose: Previous studies demonstrate that intratumoral CpG immunotherapy in combination with radiotherapy acts as an in-situ vaccine inducing antitumor immune responses capable of eradicating systemic disease. Unfortunately, most patients fail to respond. We hypothesized that immunotherapy can paradoxically upregulate immunosuppressive pathways, a phenomenon we term "rebound immune suppression," limiting clinical responses. We further hypothesized that the immunosuppressive enzyme indolamine-2,3-dioxygenase (IDO) is a mechanism of rebound immune suppression and that IDO blockade would improve immunotherapy efficacy.Experimental Design: We examined the efficacy and immunologic effects of a novel triple therapy consisting of local radiotherapy, intratumoral CpG, and systemic IDO blockade in murine models and a pilot canine clinical trial.Results: In murine models, we observed marked increase in intratumoral IDO expression after treatment with radiotherapy, CpG, or other immunotherapies. The addition of IDO blockade to radiotherapy þ CpG decreased IDO activity, reduced tumor growth, and reduced immunosuppressive factors, such as regulatory T cells in the tumor microenvironment. This triple combination induced systemic antitumor effects, decreasing metastases, and improving survival in a CD8þ T-cell-dependent manner. We evaluated this novel triple therapy in a canine clinical trial, because spontaneous canine malignancies closely reflect human cancer. Mirroring our mouse studies, the therapy was well tolerated, reduced intratumoral immunosuppression, and induced robust systemic antitumor effects. Conclusions: These results suggest that IDO maintains immune suppression in the tumor after therapy, and IDO blockade promotes a local antitumor immune response with systemic consequences. The efficacy and limited toxicity of this strategy are attractive for clinical translation. Clin Cancer Res; 22(17); 4328-40. Ó2016 AACR.
The tumor adaptive resistance to therapeutic radiation remains to be a barrier for further improvement of local cancer control. SIRT3, a member of the sirtuin family of NAD+-dependent protein deacetylases in mitochondria, promotes metabolic homeostasis through regulation of mitochondrial protein deacetylation and plays a key role in prevention of cell aging. Here, we demonstrate that SIRT3 expression is induced in an array of radiation-treated human tumor cells and their corresponding xenograft tumors including colon cancer HCT-116, glioblastoma U87 and breast cancer MDA-MB231 cells. The SIRT3 transcriptional activation is due to SIRT3 promoter activation controlled by the stress transcription factor NF-κB. Post-transcriptionally, the SIRT3 enzymatic activity is further enhanced via Thr150/Ser159 phosphorylation by Cyclin B1/CDK1, which is also induced by radiation and relocated to mitochondria together with SIRT3. Cells expressing the Thr150Ala/Ser159Ala mutant SIRT3 show a reduction in the mitochondrial protein lysine deacetylation, ΔΨm, MnSOD activity and mitochondrial ATP generation. The clonogenicity of Thr150Ala/Ser159Ala mutant transfectants is lower and significantly decreased under radiation. Tumors harboring the Thr150Ala/Ser159Ala mutant SIRT3 show inhibited growth and sensitivity to in vivo local irradiation. These results demonstrate that enhanced SIRT3 transcription and post-translational modifications in mitochondria contribute to the adaptive radioresistance in tumor cells. The CDK1-mediated SIRT3 phosphorylation is a potential effective target to sensitize tumor cells to radiotherapy.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.