Intersection of immune and oncometabolic pathways drives cancer hyperprogression during immunotherapy.

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.
Competing Interests: Declaration of interests W.Z. has served as a scientific advisor or consultant for NGM, CrownBio, Cstone, ProteoVant, Hengenix, NextCure, and Intergalactic. L.A.F receives clinical trial support from Array, Kartos, BMS, EMD Serono, and Pfizer and is a consultant for Elsevier. C.D.L. receives clinical trial support from BMS, Merck, and Novartis. A.Q. has research funding from Merck and Clovis. A.A. serves as a consultant for Merck, AstraZeneca, Bristol-Myers Squibb, and Pfizer/EMD Serono. A.A. receives research funding through the University of Michigan from Merck, Genentech, Prometheus Laboratories, Mirati Therapeutics, Roche, Bayer, Progenics, Astellas Pharma, Arcus Biosciences, AstraZeneca, Bristol-Myers Squibb, and Clovis Oncology.
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