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Updated: Jun 6, 2025
Induction and Testing of Hypoxia in Cell Culture
Published on: August 12, 2011
Hypoxia is linked to acquired resistance to immune checkpoint inhibitors in lung cancer
Camila Robles-Oteíza1, Katherine Hastings2, Jungmin Choi3,4
1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
Abstract:
Despite the established use of immune checkpoint inhibitors (ICIs) to treat non-small cell lung cancer (NSCLC), only a subset of patients benefit from treatment and ∼50% of patients whose tumors respond eventually develop acquired resistance (AR). To identify novel drivers of AR, we generated murine Msh2 knock-out (KO) lung tumors that initially responded but eventually developed AR to anti-PD-1, alone or in combination with anti-CTLA-4. Resistant tumors harbored decreased infiltrating T cells and reduced cancer cell-intrinsic MHC-I and MHC-II levels, yet remained responsive to IFNγ. Resistant tumors contained extensive regions of hypoxia, and a hypoxia signature derived from single-cell transcriptional profiling of resistant cancer cells was associated with decreased progression-free survival in a cohort of NSCLC patients treated with anti-PD-1/PD-L1 therapy. Targeting hypoxic tumor regions using a hypoxia-activated pro-drug delayed AR to ICIs in murine Msh2 KO tumors. Thus, this work provides a rationale for targeting tumor metabolic features, such as hypoxia, in combination with immune checkpoint inhibition.
Insights
Hypoxia drives acquired resistance to immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC). Targeting hypoxia can overcome resistance to ICIs, offering new therapeutic strategies for NSCLC patients.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Immune checkpoint inhibitors (ICIs) are established treatments for non-small cell lung cancer (NSCLC).
- A significant portion of NSCLC patients do not respond to ICIs, and many who initially respond develop acquired resistance (AR).
- Understanding the mechanisms of AR is crucial for improving ICI efficacy in NSCLC.
Purpose of the Study:
- To identify novel drivers of acquired resistance (AR) to immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC).
- To investigate the role of tumor microenvironment, specifically hypoxia, in ICI resistance.
- To explore therapeutic strategies targeting hypoxia to overcome AR in NSCLC.
Main Methods:
- Generation of murine Msh2 knock-out (KO) lung tumors exhibiting AR to anti-PD-1 and anti-CTLA-4 therapies.
- Analysis of immune cell infiltration, MHC-I/II expression, and hypoxia signatures in resistant tumors.
- Single-cell transcriptional profiling to identify hypoxia-associated gene expression patterns.
- Treatment of murine models with a hypoxia-activated pro-drug in combination with ICIs.
Main Results:
- Resistant tumors showed decreased T cell infiltration and reduced cancer cell-intrinsic MHC-I and MHC-II levels.
- Extensive regions of hypoxia were identified in resistant tumors.
- A hypoxia signature correlated with decreased progression-free survival in NSCLC patients treated with ICIs.
- Targeting hypoxia with a hypoxia-activated pro-drug delayed AR to ICIs in murine models.
Conclusions:
- Tumor hypoxia is a significant driver of acquired resistance to immune checkpoint inhibitors in non-small cell lung cancer.
- Targeting tumor metabolic features, such as hypoxia, in combination with ICIs represents a promising therapeutic strategy.
- This study provides a rationale for developing novel combination therapies to overcome ICI resistance in NSCLC.
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