Low-dose decitabine enhances the effect of PD-1 blockade in colorectal cancer with microsatellite stability by re-modulating the tumor microenvironment

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.

Epitherapy and immune checkpoint blockade: using epigenetic reinvigoration of exhausted and dysfunctional T cells to reimburse immunotherapy response

“…Similarly, the DNMT inhibitor decitabine enhanced lymphocyte migration and function and synergized with CTLA-4 blockade in a murine ovarian cancer model [50]. Furthermore treatment with decitabine was shown to enhance the effect of PD-1 blockade in colorectal cancer by re-modulating the tumor microenvironment [51]. Improved responses have also been observed with other classes of epigenetic drugs.…”

Comparison of Mismatch Repair Status Between Primary and Matched Metastatic Sites in Patients With Colorectal Cancer

“…In contrast, MSI-high tumors caused by MLH1 promoter methylation may be inconsistent. The level of methylation is targetable by drugs, 34 and discrepancies in methylation between primary and metastatic tumors have been reported. 35 Consistent with this assumption, we found no discrepancies in MSIhigh tumors caused by germline mutations of MMR genes, whereas one patient with a MLH1 promoter 36 and worse prognosis.…”

The local immune landscape determines tumor PD-L1 heterogeneity and sensitivity to therapy

“…Contrary to functions of NF-κB signaling, STAT1 signaling often possesses tumor suppressor functions (37,38), constitutively active STAT1 can effectively induce apoptosis and inhibit cell growth (39,40), and STAT1 is frequently downregulated in various human cancers (41,42). Therefore, a better understanding of the signaling network of PD-L1 regulation in human tumor environments would be helpful for developing rational designs of anticancer therapies that can amplify the antitumorigenic function of immune-checkpoint blockade (43)(44)(45)(46).…”