Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China.
Int J Biol Sci. 2022 Sep 6;18(15):5653-5666. doi: 10.7150/ijbs.73264. eCollection 2022.
Studies have shown that epigenetic enzymes such as histone deacetylase (HDAC) are closely related to cancers and that several HDAC inhibitors exert antitumor effects. Studies have further suggested that class IIa HDAC inhibitors are related to immune functions, including immune responses and the expression of chemokines and complement pathway components. TMP195, a selective class IIa HDAC inhibitor, has been reported to be effective against breast cancer. However, the role and mechanism of TMP195 in colorectal cancer remain unknown. In this study, we found that TMP195 significantly reduced the tumor burden in two mouse models of colitis-associated colorectal cancer (CAC) and subcutaneous tumor. Mechanistically, TMP195 decreased the proportion of total macrophages but increased the proportion of M1 macrophages by promoting polarization, resulting in the increased release of inflammatory cytokines. TMP195 had no direct effect on the proliferation of colorectal cancer cells, and its antitumor effect on the colorectal cancer disappeared when macrophages were partly depleted by clodronate liposomes. In addition, TMP195 enhanced the efficacy of PD-1 blockade. The present study revealed that the combination of TMP195 and PD-1 blockade may provide a therapeutic strategy for colorectal cancer.
研究表明，表观遗传酶如组蛋白去乙酰化酶（HDAC）与癌症密切相关，几种 HDAC 抑制剂具有抗肿瘤作用。研究进一步表明，IIa 类 HDAC 抑制剂与免疫功能有关，包括免疫反应以及趋化因子和补体途径成分的表达。TMP195 是一种选择性的 IIa 类 HDAC 抑制剂，已被报道对乳腺癌有效。然而，TMP195 在结直肠癌中的作用和机制尚不清楚。在本研究中，我们发现 TMP195 可显著减轻两种结肠炎相关结直肠癌（CAC）和皮下肿瘤小鼠模型的肿瘤负担。在机制上，TMP195 通过促进极化，降低总巨噬细胞的比例，但增加 M1 巨噬细胞的比例，导致炎症细胞因子的释放增加。TMP195 对结直肠癌细胞的增殖没有直接影响，当用氯膦酸盐脂质体部分耗尽巨噬细胞时，TMP195 对结直肠癌的抗肿瘤作用消失。此外，TMP195 增强了 PD-1 阻断的疗效。本研究揭示了 TMP195 与 PD-1 阻断的联合可能为结直肠癌提供一种治疗策略。
