小柯机器人

美国密歇根大学Weiping Zou和美国密歇根大学Rogel癌症中心Michael D. Green共同合作，近期取得重要工作进展。他们研究发现免疫治疗过程中免疫和肿瘤代谢途径的交叉驱动癌症的过度进展。相关研究成果2023年1月12日在线发表于《癌细胞》杂志上。

据介绍，免疫检查点阻断（ICB）可以产生对癌症的持久反应。研究人员和其他研究者发现，一部分患者在免疫治疗期间经历了反常的癌症快速进展。人们对ICB期间肿瘤如何加速其进展了解甚少。

在一些临床前模型中，ICB会导致高进展性疾病（HPD）。尽管免疫排斥驱动对ICB的耐药性，但与直觉相反，HPD患者和ICB后的完全缓解（CR）患者表现出相当水平的肿瘤浸润CD8⁺ T细胞和干扰素γ（IFNγ）基因特征。有趣的是，HPD而非CR患者表现出肿瘤成纤维细胞生长因子2（FGF2）和β-catenin信号的升高。在动物模型中，T细胞来源的IFNγ促进肿瘤FGF2信号传导，从而抑制PKM2活性并降低NAD⁺，导致SIRT1介导的β-catenin去乙酰化降低，并增强β-catenin的乙酰化，从而重新编程肿瘤干性。靶向IFNγ-PKM2-β-catenin轴可预防临床前模型中的HPD。

因此，核心免疫原性、代谢和致癌途径通过IFNγ-PKM2-β-catenin级联的相互作用是ICB相关HPD的基础。

附：英文原文

Title: Intersection of immune and oncometabolic pathways drives cancer hyperprogression during immunotherapy

Author: Gaopeng Li, Jae Eun Choi, Ilona Kryczek, Yilun Sun, Peng Liao, Shasha Li, Shuang Wei, Sara Grove, Linda Vatan, Reagan Nelson, Grace Schaefer, Steven G. Allen, Kamya Sankar, Leslie A. Fecher, Mishal Mendiratta-Lala, Timothy L. Frankel, Angel Qin, Jessica J. Waninger, Alangoya Tezel, Ajjai Alva, Christopher D. Lao, Nithya Ramnath, Marcin Cieslik, Paul W. Harms, Michael D. Green, Arul M. Chinnaiyan, Weiping Zou

Issue&Volume: 2023-01-12

Abstract: Immune checkpoint blockade (ICB) can produce durable responses against cancer. Weand others have found that a subset of patients experiences paradoxical rapid cancerprogression during immunotherapy. It is poorly understood how tumors can acceleratetheir progression during ICB. In some preclinical models, ICB causes hyperprogressivedisease (HPD). While immune exclusion drives resistance to ICB, counterintuitively,patients with HPD and complete response (CR) following ICB manifest comparable levelsof tumor-infiltrating CD8+ T cells and interferon γ (IFNγ) gene signature. Interestingly, patients with HPDbut not CR exhibit elevated tumoral fibroblast growth factor 2 (FGF2) and β-cateninsignaling. In animal models, T cell-derived IFNγ promotes tumor FGF2 signaling, therebysuppressing PKM2 activity and decreasing NAD+, resulting in reduction of SIRT1-mediated β-catenin deacetylation and enhanced β-cateninacetylation, consequently reprograming tumor stemness. Targeting the IFNγ-PKM2-β-cateninaxis prevents HPD in preclinical models. Thus, the crosstalk of core immunogenic,metabolic, and oncogenic pathways via the IFNγ-PKM2-β-catenin cascade underlies ICB-associatedHPD.

DOI: 10.1016/j.ccell.2022.12.008

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(22)00594-3

Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
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