PO.ET09.01 · 实验与分子治疗
组蛋白去乙酰化酶抑制剂Imofinostat与免疫检查点抑制剂联用增强结直肠癌的抗肿瘤活性
Imofinostat, a histone deacetylase inhibitor, enhances anti-tumoral activity on colorectal cancer with an immune checkpoint inhibitor
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：组蛋白去乙酰化酶（HDAC）抑制剂已被证实可发挥免疫调节作用，并增强免疫检查点抑制剂（ICI）所引发的免疫应答。Imofinostat（ABT-301）是一种对class I HDAC具有强效活性、对class IIb HDAC具有中等活性的HDAC抑制剂。本研究中，我们探讨了imofinostat联合以ICI为基础的方案在结直肠癌（CRC）中的治疗疗效及其潜在的免疫调节机制。
方法：在鼠源同基因（CT26）模型和人微卫星稳定（MSS）CRC细胞系来源异种移植（CDX）模型（HT29）中，评估imofinostat与ICI（抗mPD-1或抗PD-L1）联用（联合或不联合抗血管生成药物阿柏西普aflibercept）的效果。采用NanoString IO360面板进行转录组学分析，同时通过流式细胞术和免疫组织化学（IHC）分析免疫细胞变化及功能标志物。
结果：在CT26同基因小鼠模型中，imofinostat与avelumab（抗PD-L1）联用使8只动物中的7只出现完全肿瘤消退。值得注意的是，在达到完全缓解的动物中，7只中有6只在肿瘤再攻击后仍保持无瘤状态，表明建立了持久的抗肿瘤免疫。在平行的CT26模型中，该联合方案的疗效优于泛HDAC抑制剂伏立诺他（vorinostat）和class I选择性HDAC抑制剂西达本胺（tucidinostat）。在与患者来源PBMC共移植的HT29 CRC模型中，imofinostat与nivolumab（抗PD-1）联用观察到相加性的抗肿瘤效应，加入阿柏西普后进一步增强。基因集富集分析（GSEA）显示，imofinostat单用及联用均显著富集了与中央记忆T细胞相关的基因特征。联合治疗还增加了浸润的细胞毒性CD4⁺和CD8⁺ T细胞（IFN-gamma⁺或GzmB⁺），并减少了PBMC中的单核细胞样髓源性抑制细胞（M-MDSC）。
结论：Imofinostat通过靶向免疫抑制机制（包括减少PBMC中的M-MDSC）与ICI产生协同作用，同时促进强效的细胞毒性和记忆T细胞应答的形成。这为imofinostat联合ICI用于CRC的临床研究提供了充分的理论依据。
查看英文原文 English abstract
Background: Histone deacetylase (HDAC) inhibitors have been shown to exert immunomodulatory effects and enhance immune responses elicited by immune checkpoint inhibitors (ICIs). Imofinostat (ABT-301) is an HDAC inhibitor with potent activity against class I HDACs and moderate activity against class IIb HDACs. In this study, we investigated the therapeutic efficacy and underlying immunomodulatory mechanisms of imofinostat combined with ICI-based regimens in colorectal cancer (CRC).
Methods: Imofinostat was evaluated in combination with ICIs (anti-mPD-1 or anti-PD-L1) in both murine syngeneic (CT26) and human microsatellite stable (MSS) CRC cell line-derived xenograft (CDX) models (HT29) with or without antiangiogenic agent aflibercept. Transcriptomic profiling was performed using the NanoString IO360 panel, while immune cell alterations and functional markers were analyzed by flow cytometry and immunohistochemistry (IHC).
Results: In the CT26 syngeneic mouse model, the combination of imofinostat with avelumab (anti-PD-L1) induced complete tumor regression in 7 of 8 animals. Notably, of those achieving complete remission, 6 of 7 remained tumor-free following tumor re-challenge, indicating the establishment of durable anti-tumor immunity. This combination demonstrated superior efficacy compared to the pan-HDAC inhibitor vorinostat and the class I-selective HDAC inhibitor tucidinostat in parallel CT26 models. In the HT29 CRC model co-engrafted with patient-derived PBMCs, an additive anti-tumor effect was observed with the combination of imofinostat and nivolumab (anti-PD-1), which was further enhanced by the addition of aflibercept. Gene Set Enrichment Analysis (GSEA) revealed that imofinostat, alone and in combination, significantly enriched gene signatures associated with central memory T-cells. The combination treatment also increased infiltrated cytotoxic CD4⁺ and CD8⁺ T cells (IFN-gamma⁺ or GzmB⁺) and reduced monocytic-myeloid-derived suppressor cells (M-MDSCs) in PBMCs.
Conclusion: Imofinostat synergizes with ICI by targeting mechanisms of immune suppression, including the reduction of M-MDSCs in PBMCs, while concurrently promoting the development of robust cytotoxic and memory T-cell responses. This provides a strong rationale for the clinical investigation of imofinostat in combination with ICIs for CRC.
利益披露 Disclosure
C. Li,
AnBogen Therapeutics, Inc. Employment.
C. Wei,
AnBogen Therapeutics, Inc. Employment.
K. Tse,
AnBogen Therapeutics, Inc. Employment.
S. Huang,
AnBogen Therapeutics, Inc. Employment.
T. Yang,
AnBogen Therapeutics, Inc. Employment.
M. Lin, None..
C. Lin, None.
S. Chang,
AnBogen Therapeutics, Inc. Employment.
M. S. Horng,
AnBogen Therapeutics, Inc. Employment.
J. T. Hsu,
AnBogen Therapeutics, Inc. Employment.
K. Tan,
AnBogen Therapeutics, Inc. Employment.