Hypoxia is linked to acquired resistance to immune checkpoint inhibitors in lung cancer
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.
Authors
- Étienne Caron (ORCID: https://orcid.org/0000-0003-2770-6970)
- Gad A. Getz (ORCID: https://orcid.org/0000-0002-0936-0753)
- Taha Merghoub (ORCID: https://orcid.org/0000-0002-1518-5111)
- Fernando J. de Miguel (ORCID: https://orcid.org/0000-0002-5847-9371)
- Camila Robles-Oteíza (ORCID: https://orcid.org/0000-0001-7157-9572)
- Matthew D. Hellmann (ORCID: https://orcid.org/0000-0002-2670-9777)
- Nicholas D. Socci (ORCID: https://orcid.org/0000-0002-8254-6925)
- Katherine Hastings (ORCID: https://orcid.org/0000-0003-3319-9100)
- Francesc López‐Giráldez (ORCID: https://orcid.org/0000-0001-7476-9822)
- Francisco Expósito (ORCID: https://orcid.org/0000-0002-5406-0768)
- Arvind Ravi
- Isabelle Sirois (ORCID: https://orcid.org/0000-0002-6929-1761)
- Katerina Politi (ORCID: https://orcid.org/0000-0001-6064-4527)
- Justin F. Gainor (ORCID: https://orcid.org/0000-0001-8697-4081)
- Susan M. Kaech (ORCID: https://orcid.org/0000-0003-1674-1420)
- James Knight (ORCID: https://orcid.org/0000-0003-1166-0437)
- Jungmin Choi (ORCID: https://orcid.org/0000-0002-8614-0973)
- Mark M. Awad (ORCID: https://orcid.org/0000-0003-0928-5244)
- Hyejin Choi (ORCID: https://orcid.org/0000-0002-4884-2747)
Institutions
- Broad Institute (US)
- Salk Institute for Biological Studies (US)
- Memorial Sloan Kettering Cancer Center (US)
- Harvard University (US)
- Korea University (KR)
- Cornell University (US)
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- Swim Across America (US)
- Yale Cancer Center (US)
- Yale University (US)
- Kettering University (US)
- Massachusetts General Hospital (US)
- Parker Institute for Cancer Immunotherapy (US)
- Dana-Farber Cancer Institute (US)
- Center for Cancer Research (US)
- Molecular Oncology (United States) (US)
- Massachusetts Institute of Technology (US)
- Université de Montréal (CA)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2024-11-25
- DOI
- https://doi.org/10.1084/jem.20231106
- Citations
- 16
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 4.52
Funders
- American Association for Cancer Research
- American Cancer Society
- Yale University
- Mark Foundation For Cancer Research
- National Research Foundation
- National Research Foundation of Korea
- National Institutes of Health
- Stand Up To Cancer
- National Cancer Institute