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

ABSTRACT: 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.

SUBMITTER: Li G

PROVIDER: S-EPMC10286807 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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

Li Gaopeng G Choi Jae Eun JE Kryczek Ilona I Sun Yilun Y Liao Peng P Li Shasha S Wei Shuang S Grove Sara S Vatan Linda L Nelson Reagan R Schaefer Grace G Allen Steven G SG Sankar Kamya K Fecher Leslie A LA Mendiratta-Lala Mishal M Frankel Timothy L TL Qin Angel A Waninger Jessica J JJ Tezel Alangoya A Alva Ajjai A Lao Christopher D CD Ramnath Nithya N Cieslik Marcin M Harms Paul W PW Green Michael D MD Chinnaiyan Arul M AM Zou Weiping W

Cancer cell 20230112 2

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 ...[more]

PMID: 36638784

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Project description:ObjectiveUpdate the last known review, and summarize the definitions, diagnostic criteria, reported risk factors, possible mechanisms and potential biomarkers of hyperprogressive disease (HPD) under immunotherapy.BackgroundImmunotherapy is a relatively new systemic therapy adding a new method of treatment of especially advanced cancer patients. In a variety of immunotherapies, however, an unexpected acceleration of tumor growth, known as HPD, is observed in approximately 30% of patients after immune checkpoint inhibitor (ICI) treatment. HPD has a deleterious survival effect on patients and represents an urgent issue for both clinicians and patients. Existing literature has reviewed and summarized the definition, diagnostic criteria, reported risk factors and possible mechanisms of hyperprogression. However, with the gradual deepening of the exploration of HPD, researchers have made significant breakthroughs in elucidating the mechanism and mechanism of HPD and exploring biomarkers.MethodsThe search was conducted on Google Scholar and PubMed in January and May of 2021. We searched among English papers with no limitation on the publication year. We have included retrospective studies, case reports and basic researches related to HPD in the collection, we also referred to some review articles on HPD in recent years. A qualitative-interpretive approach was used for data extraction.ConclusionsHPD is considered to be an acceleration of tumor growth after ICI treatment that is not only due to immune infiltration but also due to real disease progression, with an incidence of about 4-30% in all retrospective published studies to date. Currently, the most widely used criteria of HPD contain Response Evaluation Criteria in Solid Tumors (RECIST) and tumor growth rate (TGR) or tumor growth kinetics. The common risk factors and underlying mechanisms of HPD have not yet been fully elucidated. However, based on the poor prognosis of HPD, there have been many advances in the exploration of biomarkers in recent years, like the prediction of HPD, such as LDH levels of peripheral blood, liquid biopsy, and radiomics, etc.

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

Publications

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

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