Background: Histone deacetylase (HDAC) inhibitors have been reported to exhibit immunomodulatory activities, including the upregulation of major histocompatibility complex class I (MHC class I). Although the immunoproteasome plays a pivotal role in MHC class I antigen presentation, its effect on immunotherapy for clear cell renal cell carcinoma (ccRCC) remains unclear. Methods: This study assessed whether OBP-801, a novel HDAC inhibitor, affects the expression of immunoproteasome subunits and subsequently the MHC class-I-mediated anti-cancer immunity in ccRCC. We analyzed the data of 531 patients with ccRCC from the Cancer Genome Atlas Kidney Clear Cell Carcinoma database. We further evaluated the treatment efficacy of the combination of OBP-801 and anti-PD-1 in a ccRCC mouse model. Results: Low molecular mass polypeptide (LMP) 2 was correlated most positively with CD3E, CD8A, and CD8B expression and estimated CD8+T cell number. In vitro studies showed that OBP-801 upregulated MHC class I presentation by inducing LMP2 expression in the ccRCC cell lines RENCA, 786-O, and Caki-1. In vivo studies in a syngeneic mouse model with subcutaneous implantation of RENCA cells showed that OBP-801 treatment increased the percentage of CD45+CD3e+T cells in tumor-infiltrating lymphocytes. The combination of anti-PD-1 antibody and OBP-801 enhanced the anti-tumor effect, LMP2 protein expression, and MHC class I presentation in tumor cells. MHC class I presentation in the tumors of each mouse was positively correlated with the percentage of CD45+CD3e+T cells. Conclusions: Our results demonstrate that OBP-801 promotes MHC class I presentation through LMP2 upregulation in tumor cells and thereby potentiates PD-1-targeting therapy. These data suggest that the combination of OBP-801 and anti-PD-1 treatment is a promising therapeutic strategy for ccRCC.
背景：组蛋白去乙酰化酶（HDAC）抑制剂已被报道具有免疫调节活性，包括上调主要组织相容性复合体I类（MHC I类）。尽管免疫蛋白酶体在MHC I类抗原呈递中起关键作用，但其对透明细胞肾细胞癌（ccRCC）免疫治疗的影响尚不清楚。方法：本研究评估了新型HDAC抑制剂OBP-801是否影响ccRCC中免疫蛋白酶体亚基的表达，进而影响MHC I类介导的抗癌免疫。我们分析了来自癌症基因组图谱肾透明细胞癌数据库的531例ccRCC患者数据。我们进一步在ccRCC小鼠模型中评估了OBP-801与抗PD-1联合治疗的疗效。结果：低分子量多肽（LMP）2与CD3E、CD8A和CD8B表达以及估计的CD8+T细胞数量呈最显著正相关。体外研究表明，OBP-801通过诱导ccRCC细胞系RENCA、786-O和Caki-1中LMP2的表达上调MHC I类呈递。在皮下植入RENCA细胞的同系小鼠模型中进行体内研究显示，OBP-801治疗增加了肿瘤浸润淋巴细胞中CD45+CD3e+T细胞的百分比。抗PD-1抗体与OBP-801联合治疗增强了抗肿瘤效果、肿瘤细胞中LMP2蛋白表达和MHC I类呈递。每只小鼠肿瘤中的MHC I类呈递与CD45+CD3e+T细胞百分比呈正相关。结论：我们的结果表明，OBP-801通过上调肿瘤细胞中的LMP2促进MHC I类呈递，从而增强PD-1靶向治疗。这些数据表明，OBP-801与抗PD-1联合治疗是ccRCC一种有前景的治疗策略。
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