Abstract
PD-1 blockade has demonstrated impressive clinical outcomes in colorectal cancers that have high microsatellite instability. However, the therapeutic efficacy for patients with tumors with low microsatellite instability or stable microsatellites needs further improvement. Here, we have demonstrated that low-dose decitabine could increase the expression of immune-related genes such as major histocompatibility complex genes and cytokine-related genes as well as the number of lymphocytes at the tumor site in CT26 colorectal cancer-bearing mice. A more significant inhibition of tumor growth and a prolongation of survival were observed in the CT26 mouse model after treatment with a combination of PD-1 blockade and decitabine than in mice treated with decitabine or PD-1 blockade alone. The anti-tumor effect of the PD-1 blockade was enhanced by low-dose decitabine. The results of RNA sequencing and whole-genome bisulfite sequencing of decitabine-treated CT26 cells and tumor samples with microsatellite stability from the patient tumor-derived xenograft model have shown that many immune-related genes, including antigen-processing and antigen-presenting genes, were upregulated, whereas the promoter demethylation was downregulated after decitabine exposure. Therefore, decitabine-based tumor microenvironment re-modulation could improve the effect of the PD-1 blockade. The application of decitabine in PD-1 blockade-based immunotherapy may elicit more potent immune responses, which can provide clinical benefits to the colorectal cancer patients with low microsatellite instability or stable microsatellites.
Highlights
IntroductionTumor immunotherapy has attracted increasing amounts of attention. Among these approaches, PD-1 blockade has shown exciting clinical outcomes in melanoma, non-small-cell lung cancer, bladder cancer, Hodgkin lymphoma and other solid tumors.[1,2,3,4,5,6,7] PD-1 blockade, which is representative of checkpoint inhibitors, has become a hot topic in the tumor immunotherapy field, its clinical effectiveness is still limited: the overall objective response rate is only 20–30%.8,9 For colorectal cancer (CRC), PD-1 blockade was not as effective as previously thought.[7,10] a group from Johns Hopkins Sidney KimmelComprehensive Cancer Center recently reported that CRC with the characteristic of high microsatellite instability (MSI-H) was sensitive to PD-1 blockade therapy.[11]
In recent years, tumor immunotherapy has attracted increasing amounts of attention
We found that the methylation level of the CT26 cells was significantly downregulated after DAC treatment (Fig. 1a)
Summary
Tumor immunotherapy has attracted increasing amounts of attention. Among these approaches, PD-1 blockade has shown exciting clinical outcomes in melanoma, non-small-cell lung cancer, bladder cancer, Hodgkin lymphoma and other solid tumors.[1,2,3,4,5,6,7] PD-1 blockade, which is representative of checkpoint inhibitors, has become a hot topic in the tumor immunotherapy field, its clinical effectiveness is still limited: the overall objective response rate is only 20–30%.8,9 For colorectal cancer (CRC), PD-1 blockade was not as effective as previously thought.[7,10] a group from Johns Hopkins Sidney KimmelComprehensive Cancer Center recently reported that CRC with the characteristic of high microsatellite instability (MSI-H) was sensitive to PD-1 blockade therapy.[11]. Tumor immunotherapy has attracted increasing amounts of attention. Among these approaches, PD-1 blockade has shown exciting clinical outcomes in melanoma, non-small-cell lung cancer, bladder cancer, Hodgkin lymphoma and other solid tumors.[1,2,3,4,5,6,7] PD-1 blockade, which is representative of checkpoint inhibitors, has become a hot topic in the tumor immunotherapy field, its clinical effectiveness is still limited: the overall objective response rate is only 20–30%.8,9. Comprehensive Cancer Center recently reported that CRC with the characteristic of high microsatellite instability (MSI-H) was sensitive to PD-1 blockade therapy.[11] Later, in May 2017, the US Food and Drug
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