Department of Surgery, University of Michigan, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA.
Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Cancer Cell. 2023 Feb 13;41(2):304-322.e7. doi: 10.1016/j.ccell.2022.12.008. Epub 2023 Jan 12.
Immune checkpoint blockade (ICB) can produce durable responses against cancer. We and others have found that a subset of patients experiences paradoxical rapid cancer progression during immunotherapy. It is poorly understood how tumors can accelerate their progression during ICB. In some preclinical models, ICB causes hyperprogressive disease (HPD). While immune exclusion drives resistance to ICB, counterintuitively, patients with HPD and complete response (CR) following ICB manifest comparable levels of tumor-infiltrating CD8 T cells and interferon γ (IFNγ) gene signature. Interestingly, patients with HPD but not CR exhibit elevated tumoral fibroblast growth factor 2 (FGF2) and β-catenin signaling. In animal models, T cell-derived IFNγ promotes tumor FGF2 signaling, thereby suppressing PKM2 activity and decreasing NAD, resulting in reduction of SIRT1-mediated β-catenin deacetylation and enhanced β-catenin acetylation, consequently reprograming tumor stemness. Targeting the IFNγ-PKM2-β-catenin axis prevents HPD in preclinical models. Thus, the crosstalk of core immunogenic, metabolic, and oncogenic pathways via the IFNγ-PKM2-β-catenin cascade underlies ICB-associated HPD.
免疫检查点阻断（ICB）可以针对癌症产生持久的反应。我们和其他人发现，一部分患者在免疫治疗期间经历了矛盾的快速癌症进展。目前还不清楚肿瘤如何在 ICB 期间加速其进展。在一些临床前模型中，ICB 会导致超进展性疾病（HPD）。虽然免疫排斥会导致对 ICB 的耐药性，但具有讽刺意味的是，在接受 ICB 后出现 HPD 和完全缓解（CR）的患者表现出可比水平的肿瘤浸润 CD8 T 细胞和干扰素 γ（IFNγ）基因特征。有趣的是，出现 HPD 但没有 CR 的患者表现出升高的肿瘤成纤维细胞生长因子 2（FGF2）和 β-连环蛋白信号。在动物模型中，T 细胞衍生的 IFNγ 促进肿瘤 FGF2 信号，从而抑制 PKM2 活性并降低 NAD，导致 SIRT1 介导的 β-连环蛋白去乙酰化减少和 β-连环蛋白乙酰化增加，进而重新编程肿瘤干性。针对 IFNγ-PKM2-β-连环蛋白轴可预防临床前模型中的 HPD。因此，IFNγ-PKM2-β-连环蛋白级联通过核心免疫、代谢和致癌途径的串扰是 ICB 相关 HPD 的基础。
