Hypoxia is linked to acquired resistance to immune checkpoint inhibitors in lung cancer Journal Article
| Authors: | Robles-Oteíza, C.; Hastings, K.; Choi, J.; Sirois, I.; Ravi, A.; Expósito, F.; de Miguel, F.; Knight, J. R.; López-Giráldez, F.; Choi, H.; Socci, N. D.; Merghoub, T.; Awad, M.; Getz, G.; Gainor, J.; Hellmann, M. D.; Caron, E.; Kaech, S. M.; Politi, K. |
| Article Title: | Hypoxia is linked to acquired resistance to immune checkpoint inhibitors in lung cancer |
| 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 similar to 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 IFN gamma. 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. |
| Keywords: | chemotherapy; immunotherapy; tumor hypoxia; sensitivity; combination; nivolumab; evofosfamide; pd-1 blockade; anti-pd-1 therapy; activated prodrug |
| Journal Title: | Journal of Experimental Medicine |
| Volume: | 222 |
| Issue: | 1 |
| ISSN: | 0022-1007 |
| Publisher: | Rockefeller University Press |
| Date Published: | 2025-01-06 |
| Start Page: | e20231106 |
| Language: | English |
| ACCESSION: | WOS:001362673700001 |
| DOI: | 10.1084/jem.20231106 |
| PROVIDER: | wos |
| PMCID: | PMC11602551 |
| PUBMED: | 39585348 |
| Notes: | Article -- Source: Wos |
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