癌症研究
免疫疗法
封锁
免疫系统
免疫检查点
癌症免疫疗法
CD8型
癌症
医学
免疫学
内科学
受体
作者
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,K. Nathan Sankar,Leslie A. Fecher,Mishal Mendiratta‐Lala,Timothy L. Frankel,Angel Qin,Jessica Waninger,Alangoya Tezel,Ajjai Alva
出处
期刊:Cancer Cell
[Cell Press]
日期:2023-01-12
卷期号:41 (2): 304-322.e7
被引量:87
标识
DOI:10.1016/j.ccell.2022.12.008
摘要
Summary
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.
科研通智能强力驱动
Strongly Powered by AbleSci AI