Intersection of immune and oncometabolic pathways drives cancer hyperprogression during immunotherapy

• Published in: Cancer cell Vol. 41; no. 2; pp. 304 - 322.e7
• Main Authors: Li, Gaopeng, Choi, Jae Eun, Kryczek, Ilona, Sun, Yilun, Liao, Peng, Li, Shasha, Wei, Shuang, Grove, Sara, Vatan, Linda, Nelson, Reagan, Schaefer, Grace, Allen, Steven G., Sankar, Kamya, Fecher, Leslie A., Mendiratta-Lala, Mishal, Frankel, Timothy L., Qin, Angel, Waninger, Jessica J., Tezel, Alangoya, Alva, Ajjai, Lao, Christopher D., Ramnath, Nithya, Cieslik, Marcin, Harms, Paul W., Green, Michael D., Chinnaiyan, Arul M., Zou, Weiping
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.02.2023
• Subjects: Animals; beta Catenin; CD8-Positive T-Lymphocytes; complete response; Disease Progression; FGF2; Fibroblast Growth Factor 2; glycolytic metabolism; hyperprogressive disease; IFNγ; immune checkpoint blockade; Immunotherapy - methods; Interferon-gamma; Neoplasms - pathology; Neoplasms - therapy; oncogenesis; PD-L1/PD-1 pathway; T cell immunity; β-catenin; IFNγ; β-catenin; oncogenesis; T cell immunity; complete response; glycolytic metabolism; FGF2; PD-L1/PD-1 pathway; hyperprogressive disease; immune checkpoint blockade
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2022.12.008

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. [Display omitted] •Hyperprogressive disease (HPD) occurs during immunotherapy•HPD is associated with high levels of IFNγ, FGF2, and β-catenin signaling•CD8+ T cell derived IFNγ promotes HPD via rewiring cancer oncometabolic pathways•High IFNγ-FGF2-β-catenin signature is a potential biomarker and target for HPD Li et al. uncover crosstalk between core immunogenic, metabolic, and oncogenic pathways in cancer cells during immunotherapy, which enables hyperprogressive disease (HPD) in preclinical models and correlates with immunotherapy-associated HPD in patients with cancer.