Liang Rongpu, Ding Dongbing, Li Yiquan, Lan Tianyun, Ryabtseva Svetlana, Huang Shengxin, Ren Jiannan, Huang He, Wei Bo
Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510630, P.R. China.
Department of Gastrointestinal Surgery, Lingnan Hospital, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China.
J Nanobiotechnology. 2024 Dec 16;22(1):753. doi: 10.1186/s12951-024-02936-0.
Immunotherapy for colorectal cancer (CRC) with microsatellite stability (MSS) and mismatch repair proficiency (pMMR) has shown limited success in clinical trials. The combination of immunomodulators and immune checkpoint inhibitors (ICIs) is a potential strategy for treating CRC.
Histone deacetylase (HDAC) and indoleamine 2,3-dioxygenase 1 (IDO1) expression in CRC tissues and adjacent normal tissues was analyzed via database analysis, immunohistochemistry, and western blotting. A nanodrug designated as NP-I/P was subsequently formulated, encapsulating an IDO1 inhibitor (IDO1i; namely, epacadostat) and an immunomodulatory HDAC inhibitor (HDACi; namely, panobinostat). The antitumor efficacy of the nanoparticles and their effects on tumor microenvironment features were evaluated via in vitro and in vivo experiments.
In the present study, we found that HDAC overexpression and IDO1 expression were attenuated in MSS/pMMR CRC. Thus, a nanodrug designated as NP-I/P was formulated to encapsulate epacadostat and panobinostat. In vitro, NP-I/P treatment promoted the apoptosis of tumor cells and induced the release of damage-associated molecular patterns, thereby leading to cell death-associated immune activation. The in vivo results revealed that NP-I/P treatment reversed the immunosuppressive phenotype of the microenvironment by inducing tumor immunogenic cell death (ICD), promoting CD8 T cell infiltration, and reducing the numbers of Tregs, tumor-associated macrophages, and myeloid-derived suppressor cells. Finally, the results of the patient-derived xenograft and patient-derived organoid models demonstrated that NP-I/P treatment triggered tumor cell death and modulated the immune microenvironment in human CRC.
The combination of IDO1 and HDAC inhibitors represents a promising strategy for CRC treatment, and NP-I/P is a candidate for clinical trials.
微卫星稳定（MSS）和错配修复功能正常（pMMR）的结直肠癌（CRC）免疫治疗在临床试验中取得的成功有限。免疫调节剂与免疫检查点抑制剂（ICI）联合使用是治疗CRC的一种潜在策略。
通过数据库分析、免疫组织化学和蛋白质印迹法分析CRC组织及相邻正常组织中组蛋白脱乙酰酶（HDAC）和吲哚胺2,3-双加氧酶1（IDO1）的表达。随后制备了一种名为NP-I/P的纳米药物，其包裹了一种IDO1抑制剂（IDO1i；即依帕司他）和一种免疫调节性HDAC抑制剂（HDACi；即帕比司他）。通过体外和体内实验评估了纳米颗粒的抗肿瘤疗效及其对肿瘤微环境特征的影响。
在本研究中，我们发现HDAC的过表达和IDO1的表达在MSS/pMMR CRC中减弱。因此，制备了一种名为NP-I/P的纳米药物来包裹依帕司他和帕比司他。在体外，NP-I/P处理促进肿瘤细胞凋亡并诱导损伤相关分子模式的释放，从而导致与细胞死亡相关的免疫激活。体内结果显示，NP-I/P处理通过诱导肿瘤免疫原性细胞死亡（ICD）、促进CD8 T细胞浸润以及减少调节性T细胞、肿瘤相关巨噬细胞和骨髓来源的抑制性细胞数量，逆转了微环境的免疫抑制表型。最后，患者来源的异种移植模型和患者来源的类器官模型结果表明，NP-I/P处理引发了人CRC中的肿瘤细胞死亡并调节了免疫微环境。
IDO1和HDAC抑制剂联合使用是一种有前景的CRC治疗策略，NP-I/P是一种临床试验候选药物。
