Decitabine Augments Chemotherapy-Induced PD-L1 Upregulation for PD-L1 Blockade in Colorectal Cancer
Decitabine Augments Chemotherapy-Induced PD-L1 Upregulation for PD-L1 Blockade in Colorectal Cancer
复制标题
DOI：
10.3390/cancers12020462
复制
发表时间：
2020-02-01
期刊：
影响因子：
5.2
通讯作者：
Chao, K. S. Clifford
中科院分区：
文献类型：
--
作者：
Huang, Kevin Chih-Yang;Chiang, Shu-Fen;Chao, K. S. Clifford
程序性细胞死亡-1（PD-1）在几种恶性肿瘤中表现出令人印象深刻的临床结果，但其在大多数结直肠癌中的治疗效果仍然很低。因此，如何提高其在结直肠癌（CRC）患者中的治疗效果需要进一步研究。在这里，我们证明了免疫原性化疗药物在体外和体内触发肿瘤PD-L1表达的诱导，这一事实在接受术前新辅助化疗（neoCT）治疗的转移性CRC患者中得到了验证，表明通过化疗方案上调肿瘤PD-L1通过PD-1/PD-L1免疫治疗更可行。然而，我们发现肿瘤PD-L1通过DNA甲基转移酶1（DNMT 1）的表观遗传控制显着影响化疗的反应。我们证明，地西他滨（DAC）诱导DNA低甲基化，这不仅直接增强肿瘤PD-L1表达，而且增加免疫相关基因的表达和肿瘤内T细胞浸润在体外和体内。DAC被发现可以显著增强PD-L1免疫疗法的治疗效果，以抑制肿瘤生长并延长体内生存期。由此可见，DAC通过直接触发肿瘤PD-L1表达，引发更强的抗癌免疫应答，重塑肿瘤微环境，提高PD-L1免疫治疗的效果，未来为CRC患者提供潜在的临床获益。
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.