KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance

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  • Anastasia Maria Zavitsanou
  • Ray Pillai
  • Yuan Hao
  • Warren L. Wu
  • Eric Bartnicki
  • Triantafyllia Karakousi
  • Sahith Rajalingam
  • Alberto Herrera
  • Angeliki Karatza
  • Ali Rashidfarrokhi
  • Sabrina Solis
  • Metamia Ciampricotti
  • Anna H. Yeaton
  • Ellie Ivanova
  • Corrin A. Wohlhieter
  • Makiko Hayashi
  • Burcu Karadal-Ferrena
  • Harvey I. Pass
  • John T. Poirier
  • Charles M. Rudin
  • Kwok Kin Wong
  • Andre L. Moreira
  • Kamal M. Khanna
  • Aristotelis Tsirigos
  • Thales Papagiannakopoulos
  • Sergei B. Koralov

Lung cancer treatment has benefited greatly through advancements in immunotherapies. However, immunotherapy often fails in patients with specific mutations like KEAP1, which are frequently found in lung adenocarcinoma. We established an antigenic lung cancer model and used it to explore how Keap1 mutations remodel the tumor immune microenvironment. Using single-cell technology and depletion studies, we demonstrate that Keap1-mutant tumors diminish dendritic cell and T cell responses driving immunotherapy resistance. This observation was corroborated in patient samples. CRISPR-Cas9-mediated gene targeting revealed that hyperactivation of the NRF2 antioxidant pathway is responsible for diminished immune responses in Keap1-mutant tumors. Importantly, we demonstrate that combining glutaminase inhibition with immune checkpoint blockade can reverse immunosuppression, making Keap1-mutant tumors susceptible to immunotherapy. Our study provides new insight into the role of KEAP1 mutations in immune evasion, paving the way for novel immune-based therapeutic strategies for KEAP1-mutant cancers.

Original languageEnglish
Article number113295
JournalCell Reports
Issue number11
Pages (from-to)1-25
Publication statusPublished - 28 Nov 2023

Bibliographical note

Publisher Copyright:
© 2023 The Author(s)

    Research areas

  • adenocarcinoma, CD103 DC, CP: Cancer, CP: Immunology, immune surveillance, immunotherapy, KEAP1, LUAD, lung cancer, NRF2, NSCLC, T cell

ID: 373833137