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Decitabine Augments Chemotherapy-Induced PD-L1 Upregulation for PD-L1 Blockade in Colorectal Cancer.

ABSTRACT: Programmed cell death-1 (PD-1) has demonstrated impressive clinical outcomes in several malignancies, but its therapeutic efficacy in the majority of colorectal cancers is still low. Therefore, methods to improve its therapeutic efficacy in colorectal cancer (CRC) patients need further investigation. Here, we demonstrate that immunogenic chemotherapeutic agents trigger the induction of tumor PD-L1 expression in vitro and in vivo, a fact which was validated in metastatic CRC patients who received preoperatively neoadjuvant chemotherapy (neoCT) treatment, suggesting that tumor PD-L1 upregulation by chemotherapeutic regimen is more feasible via PD-1/PD-L1 immunotherapy. However, we found that the epigenetic control of tumor PD-L1 via DNA methyltransferase 1 (DNMT1) significantly influenced the response to chemotherapy. We demonstrate that decitabine (DAC) induces DNA hypomethylation, which not only directly enhances tumor PD-L1 expression but also increases the expression of immune-related genes and intratumoral T cell infiltration in vitro and in vivo. DAC was found to profoundly enhance the therapeutic efficacy of PD-L1 immunotherapy to inhibit tumor growth and prolong survival in vivo. Therefore, it can be seen that DAC remodels the tumor microenvironment to improve the effect of PD-L1 immunotherapy by directly triggering tumor PD-L1 expression and eliciting stronger anti-cancer immune responses, providing potential clinical benefits to CRC patients in the future.

SUBMITTER: Huang KC

PROVIDER: S-EPMC7072566 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Decitabine Augments Chemotherapy-Induced PD-L1 Upregulation for PD-L1 Blockade in Colorectal Cancer.

Huang Kevin Chih-Yang KC Chiang Shu-Fen SF Chen William Tzu-Liang WT Chen Tsung-Wei TW Hu Ching-Han CH Yang Pei-Chen PC Ke Tao-Wei TW Chao K S Clifford KSC

Cancers 20200217 2

Programmed cell death-1 (PD-1) has demonstrated impressive clinical outcomes in several malignancies, but its therapeutic efficacy in the majority of colorectal cancers is still low. Therefore, methods to improve its therapeutic efficacy in colorectal cancer (CRC) patients need further investigation. Here, we demonstrate that immunogenic chemotherapeutic agents trigger the induction of tumor PD-L1 expression in vitro and in vivo, a fact which was validated in metastatic CRC patients who received ...[more]

PMID: 32079180

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Project description:The property of drug-resistance may attenuate clinical therapy in cancer cells, such as chemoresistance to gefitinib in colon cancer cells. In previous studies, overexpression of PD-L1 causes proliferation and metastasis in cancer cells; therefore, the PD-L1 pathway allows tumor cells to exert an adaptive resistance mechanism in vivo. Nano-diamino-tetrac (NDAT) has been shown to enhance the anti-proliferative effect induced by first-line chemotherapy in various types of cancer, including colorectal cancer (CRC). In this work, we attempted to explore whether NDAT could enhance the anti-proliferative effect of gefitinib in CRC and clarified the mechanism of their interaction. The MTT assay was utilized to detect a reduction in cell proliferation in four primary culture tumor cells treated with gefitinib or NDAT. The gene expression of PD-L1 and other tumor growth-related molecules were quantified by quantitative polymerase chain reaction (qPCR). Furthermore, the identification of PI3K and PD-L1 in treated CRC cells were detected by western blotting analysis. PD-L1 presentation in HCT116 xenograft tumors was characterized by specialized immunohistochemistry (IHC) and the hematoxylin and eosin stain (H&E stain). The correlations between the change in PD-L1 expression and tumorigenic characteristics were also analyzed. (3) The PD-L1 was highly expressed in Colo_160224 rather than in the other three primary CRC cells and HCT-116 cells. Moreover, the PD-L1 expression was decreased by gefitinib (1 µM and 10 µM) in two cells (Colo_150624 and 160426), but 10 µM gefitinib stimulated PD-L1 expression in gefitinib-resistant primary CRC Colo_160224 cells. Inactivated PI3K reduced PD-L1 expression and proliferation in CRC Colo_160224 cells. Gefitinib didn't inhibit PD-L1 expression and PI3K activation in gefitinib-resistant Colo_160224 cells. However, NDAT inhibited PI3K activation as well as PD-L1 accumulation in gefitinib-resistant Colo_160224 cells. The combined treatment of NDAT and gefitinib inhibited pPI3K and PD-L1 expression and cell proliferation. Additionally, NDAT reduced PD-L1 accumulation and tumor growth in the HCT116 (K-RAS mutant) xenograft experiment. (4) Gefitinib might suppress PD-L1 expression but did not inhibit proliferation through PI3K in gefitinib-resistant primary CRC cells. However, NDAT not only down-regulated PD-L1 expression via blocking PI3K activation but also inhibited cell proliferation in gefitinib-resistant CRCs.

Dataset Information

Decitabine Augments Chemotherapy-Induced PD-L1 Upregulation for PD-L1 Blockade in Colorectal Cancer.

Publications

Decitabine Augments Chemotherapy-Induced PD-L1 Upregulation for PD-L1 Blockade in Colorectal Cancer.

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