Intersection of immune and oncometabolic pathways drives cancer hyperprogression during immunotherapy

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; Kamya Sankar; Leslie A Fecher; Mishal Mendiratta-Lala; Timothy L Frankel; Angel Qin; Jessica J Waninger; Alangoya Tezel; Ajjai Alva; Christopher D Lao; Nithya Ramnath; Marcin Cieslik; Paul W Harms; Michael D Green; Arul M Chinnaiyan; Weiping Zou

doi:10.1016/j.ccell.2022.12.008

Intersection of immune and oncometabolic pathways drives cancer hyperprogression during immunotherapy

Cancer Cell. 2023 Feb 13;41(2):304-322.e7. doi: 10.1016/j.ccell.2022.12.008. Epub 2023 Jan 12.

Authors

Gaopeng Li¹, Jae Eun Choi², Ilona Kryczek¹, Yilun Sun³, Peng Liao¹, Shasha Li¹, Shuang Wei¹, Sara Grove¹, Linda Vatan¹, Reagan Nelson⁴, Grace Schaefer⁴, Steven G Allen⁴, Kamya Sankar⁵, Leslie A Fecher⁵, Mishal Mendiratta-Lala⁴, Timothy L Frankel⁶, Angel Qin⁵, Jessica J Waninger⁷, Alangoya Tezel⁴, Ajjai Alva⁸, Christopher D Lao⁵, Nithya Ramnath⁹, Marcin Cieslik¹⁰, Paul W Harms¹¹, Michael D Green¹², Arul M Chinnaiyan¹³, Weiping Zou¹⁴

Affiliations

¹ 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.
² Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
³ Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA; Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
⁴ Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
⁵ Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
⁶ Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
⁷ Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
⁸ Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
⁹ Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, USA.
¹⁰ Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
¹¹ Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
¹² Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA; Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, USA; Graduate Program in Immunology, University of Michigan, Ann Arbor, MI, USA; Graduate Program in Cancer Biology, University of Michigan, Ann Arbor, MI, USA. Electronic address: [email protected].
¹³ Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, MI, USA.
¹⁴ 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; Graduate Program in Immunology, University of Michigan, Ann Arbor, MI, USA; Graduate Program in Cancer Biology, University of Michigan, Ann Arbor, MI, USA. Electronic address: [email protected].

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.

Keywords: FGF2; IFNγ; PD-L1/PD-1 pathway; T cell immunity; complete response; glycolytic metabolism; hyperprogressive disease; immune checkpoint blockade; oncogenesis; β-catenin.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural

MeSH terms

Animals
CD8-Positive T-Lymphocytes
Disease Progression
Fibroblast Growth Factor 2
Immunotherapy / methods
Interferon-gamma
Neoplasms* / pathology
Neoplasms* / therapy
beta Catenin*

Substances

beta Catenin
Fibroblast Growth Factor 2
Interferon-gamma

Abstract

Publication types

MeSH terms

Substances

Grants and funding