PDF(Pubmed)
Abstract：
Immunotherapy has shown promising clinical results in clear cell renal cell carcinoma (ccRCC), but low clinical target response rates due to dysfunction of the major histocompatibility complex (MHC) and an inhibitory tumor immune microenvironment (TIME) have largely limited the associated clinical benefits. In the present study, we explored the feasibility of enhancing tumor-specific-MHC-II-HLA-DRA expression, counteracting the TIME\'s suppressive effects, thereby improving the sensitivity of immune checkpoint inhibitor (ICI) therapy from the standpoint of cuproptosis. Immunohistochemical staining and in vitro experiments validated the expression of HLA-DRA in ccRCC and its positive impact on ICI therapy. Subsequently, we observed that cuproptosis upregulated HLA-DRA expression in a dose-dependent manner, further confirming the link between cuproptosis and HLA-DRA. In vivo experiments showed that cuproptosis increased the sensitivity to ICI treatment, and implementing cuproptosis alongside anti-PD-1 treatment curtailed tumor growth. Mechanistically, cuproptosis upregulates HLA-DRA expression at the transcriptional level in a dose-dependent manner by inducing the production of reactive oxygen species; high levels of HLA-DRA promote the expression of chemokines CCL5, CXCL9, and CXCL10 in the TIME, inhibiting the development of a pro-tumor microenvironment by promoting the infiltration of CD4+T and CD8+T cells, thereby synergizing ICI therapy and exerting anti-tumor effects. Taken together, this work highlights the role of cuproptosis in mediating TIME remodeling and synergistic immunotherapy, providing new evidence that cuproptosis can evoke effective anti-tumor immune responses.
摘要：
免疫治疗在透明细胞肾细胞癌（ccRCC）中显示出有希望的临床结果，但由于主要组织相容性复合体(MHC)的功能障碍和抑制性肿瘤免疫微环境(TIME)导致的低临床目标反应率在很大程度上限制了相关的临床获益.在本研究中,我们探讨了增强肿瘤特异性MHC-II-HLA-DRA表达的可行性，抵消时间的抑制作用，从而提高免疫检查点抑制剂（ICI）治疗的敏感性从角化的角度来看。免疫组织化学染色和体外实验验证了HLA-DRA在ccRCC中的表达及其对ICI治疗的积极影响。随后，我们观察到细胞凋亡以剂量依赖性方式上调HLA-DRA表达,进一步证实角化和HLA-DRA之间的联系。体内实验表明，角化增加了对ICI治疗的敏感性，并在抗PD-1治疗的同时实施角化抑制了肿瘤的生长。机械上,角化通过诱导活性氧的产生以剂量依赖性方式在转录水平上调HLA-DRA表达;高水平的HLA-DRA促进趋化因子CCL5，CXCL9和CXCL10在TIME的表达，通过促进CD4+T和CD8+T细胞的浸润来抑制肿瘤微环境的发展，从而协同ICI治疗并发挥抗肿瘤作用。一起来看,这项工作强调了角化在介导时间重塑和协同免疫疗法中的作用，提供了新的证据表明，角化可以引起有效的抗肿瘤免疫反应。
