Tumor hypoxia is associated with resistance to PD-1 blockade in squamous cell carcinoma of the head and neck
Open accessAbstract
The majority of patients with recurrent/metastatic squamous cell carcinoma of the head and neck (HNSCC) (R/M) do not benefit from anti-PD-1 therapy. Hypoxia induced immunosuppression may be a barrier to immunotherapy. Therefore, we examined the metabolic effect of anti-PD-1 therapy in a murine MEER HNSCC model as well as intratumoral hypoxia in R/M patients. In order to characterize the tumor microenvironment in PD-1 resistance, a MEER cell line was created from the parental line that are completely resistant to anti-PD-1. These cell lines were then metabolically profiled using seahorse technology and injected into C57/BL6 mice. After tumor growth, mice were pulsed with pimonidazole and immunofluorescent imaging was performed to analyze hypoxia and T cell infiltration. To validate the preclinical results, we analyzed tissues from R/M patients (n=36) treated with anti-PD-1 mAb, via immunofluorescent imaging for number of CD8+ T cells (CD8), Tregs and the percent area (CAIX) and mean intensity (I) of carbonic anhydrase IX in tumor. We analyzed disease control rate (DCR), progression free survival (PFS), and overall survival (OS) using proportional odds and proportional hazards (Cox) regression. We found that anti-PD-1 resistant MEER has significantly higher oxidative metabolism, while there was no difference in glycolytic metabolism. Intratumoral hypoxia was significantly increased and CD8+ T cells decreased in anti-PD-1 resistant tumors compared with parental tumors in the same mouse. In R/M patients, lower tumor hypoxia by CAIX/I was significantly associated with DCR (p=0.007), PFS, and OS, and independently associated with response (p=0.028) and PFS (p=0.04) in a multivariate model including other significant immune factors. During PD-1 resistance, tumor cells developed increased oxidative metabolism leading to increased intratumoral hypoxia and a decrease in CD8+ T cells. Lower tumor hypoxia was independently associated with increased efficacy of anti-PD-1 therapy in patients with R/M HNSCC. To our knowledge this is the first analysis of the effect of hypoxia in this patient population and highlights its importance not only as a predictive biomarker but also as a potential target for therapeutic intervention.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Zandberg et al. reported that in an animal model of HNSCC, disease control rate and survival were altered in mice with intra-tumoral hypoxia, rendering them resistant to anti-PD-1 immunotherapy.
“Zandberg et al. reported that in an animal model of HNSCC, disease control rate (DCR) and survival were altered in mice with intra-tumoral hypoxia, rendering them resistant to anti-PD-1 immunotherapy [128].”
From Immune Checkpoint Inhibitors in Cancer Therapy (2022) · cites this paper as [128]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)
Eisenhauer, E. A., Therasse, P., Bogaerts, J., Schwartz, L. H., Sargent, D., Ford, R., Dancey, J., Arbuck, S., Gwyther, S., Mooney, M., et al. (2009) · European Journal of Cancer · doi:10.1016/j.ejca.2008.10.026 · Cited by 29,534 · see citing works
Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck
Ferris, R. L., Blumenschein, G., Fayette, J., Guigay, J., Colevas, A. D., Licitra, L., Harrington, K., Kasper, S., Vokes, E. E., Even, C., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1602252 · Cited by 5,101 · see citing works
Self-citationBurtness, B., Harrington, K. J., Greil, R., Soulières, D., Tahara, M., de Castro, G., Psyrri, A., Basté, N., Neupane, P., Bratland, Å., et al. (2019) · The Lancet · doi:10.1016/s0140-6736(19)32591-7 · Cited by 3,336 · see citing works
Seiwert, T. Y., Burtness, B., Mehra, R., Weiss, J., Berger, R., Eder, J. P., Heath, K., McClanahan, T., Lunceford, J., Gause, C., et al. (2016) · The Lancet Oncology · doi:10.1016/s1470-2045(16)30066-3 · Cited by 1,745 · see citing works
Cohen, E., Soulières, D., le Tourneau, C., Dinis, J., Licitra, L., Ahn, M., Soria, A., Machiels, J., Mach, N., Mehra, R., et al. (2019) · The Lancet · doi:10.1016/s0140-6736(18)31999-8 · Cited by 1,423 · see citing works
Ferris, R. L., Blumenschein, G. R., Fayette, J., Guigay, J., Colevas, A. D., Licitra, L. F., Harrington, K. J., Kasper, S., Vokes, E. E., Even, C., et al. (2018) · Oral Oncology · doi:10.1016/j.oraloncology.2018.04.008 · Cited by 807 · see citing works
Self-citationScharping, N. E., Menk, A. V., Moreci, R. S., Whetstone, R. D., Dadey, R., Watkins, S. C., Ferris, R. L., & Delgoffe, G. M. (2016) · Immunity · doi:10.1016/j.immuni.2016.08.009 · Cited by 705 · see citing works
Self-citationImmune Landscape of Viral- and Carcinogen-Driven Head and Neck Cancer
Cillo, A. R., Kürten, C. H. L., Tabib, T., Qi, Z., Onkar, S., Wang, T., Liu, A., Duvvuri, U., Kim, S., Soose, R. J., et al. (2020) · Immunity · doi:10.1016/j.immuni.2019.11.014 · Cited by 654 · see citing works
Self-citationKulangara, K., Zhang, N., Corigliano, E., Guerrero, L., Waldroup, S. A., Jaiswal, D., Jansson, M., Shah, S., Hanks, D. A., Wang, J., et al. (2018) · Archives of Pathology & Laboratory Medicine · doi:10.5858/arpa.2018-0043-oa · Cited by 538 · see citing works
Immune suppressive mechanisms in the tumor microenvironment
Munn, D. H., & Bronte, V. (2015) · Current Opinion in Immunology · doi:10.1016/j.coi.2015.10.009 · Cited by 519 · see citing works
Zhao, E., Maj, T., Kryczek, I., Li, W., Wu, K., Zhao, L., Wei, S., Crespo, J., Wan, S., Vatan, L., et al. (2016) · Nature Immunology · doi:10.1038/ni.3313 · Cited by 405 · see citing works
Immunotherapy for head and neck cancer: Recent advances and future directions
Cramer, J. D., Burtness, B. A., & Ferris, R. L. (2019) · Oral Oncology · doi:10.1016/j.oraloncology.2019.104460 · Cited by 307 · see citing works
Self-citationTumor cell oxidative metabolism as a barrier to PD-1 blockade immunotherapy in melanoma
Najjar, Y. G., Menk, A. V., Sander, C., Rao, U. N. M., Karunamurthy, A. D., Bhatia, R., Zhai, S., Kirkwood, J. M., & Delgoffe, G. M. (2019) · JCI Insight · doi:10.1172/jci.insight.124989 · Cited by 234 · see citing works
Self-citationMetabolic Switch in the Tumor Microenvironment Determines Immune Responses to Anti-cancer Therapy
Wegiel, B., Vuerich, M., Daneshmandi, S., & Seth, P. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00284 · Cited by 125 · see citing works
Tumor Microenvironment Metabolism: A New Checkpoint for Anti-Tumor Immunity
Scharping, N. E., & Delgoffe, G. M. (2016) · Vaccines · doi:10.3390/vaccines4040046 · Cited by 119 · see citing works
Self-citationBrooks, J. M., de Menezes, A. N., Ibrahim, M., Archer, L., Lal, N., Bagnall, C. J., von Zeidler, S. V., Valentine, H. R., Spruce, R. J., Batis, N., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-3314 · Cited by 109 · see citing works
Current relevance of hypoxia in head and neck cancer
Bredell, M., Ernst, J., Kochairi, I. E., Dahlem, Y., Ikenberg, K., & Schumann, D. (2016) · Oncotarget · doi:10.18632/oncotarget.9549 · Cited by 93 · see citing works
Hoover, A. C., Spanos, W. C., Harris, G. F., et al. (2007) · Archives of Otolaryngology - Head and Neck Surgery · doi:10.1001/archotol.133.5.495 · Cited by 87 · see citing works
Antitumor T-cell Reconditioning: Improving Metabolic Fitness for Optimal Cancer Immunotherapy
Rivadeneira, D. B., & Delgoffe, G. M. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-0894 · Cited by 68 · see citing works
Self-citationHartman, D. J., Ahmad, F., Ferris, R. L., Rimm, D. L., & Pantanowitz, L. (2018) · Oral Oncology · doi:10.1016/j.oraloncology.2018.10.005 · Cited by 41 · see citing works
Self-citationAbstract LB-339: Biomarkers predictive of response to pembrolizumab in head and neck cancer (HNSCC)
Seiwert, T. Y., Haddad, R. I., Bauml, J. M., Weiss, J., Pfister, D. G., Gupta, S., Mehra, R., Gluck, I., Kang, H., Worden, F. P., et al. (2018) · Cancer Research · doi:10.1158/1538-7445.am2018-lb-339 · Cited by 38 · see citing works
Immunohistochemical Detection of Tumour Hypoxia
Young, R. J., & Möller, A. (2009) · Methods in molecular biology · doi:10.1007/978-1-60327-345-9_12 · Cited by 23 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions
Chen, Z., Han, F., Du, Y., Shi, H., & Zhou, W. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01332-8 · Cited by 1,612 · see citing works
Immune Checkpoint Inhibitors in Cancer Therapy
Shiravand, Y., Khodadadi, F., Kashani, S. M. A., Hosseini-Fard, S. R., Hosseini, S., Sadeghirad, H., Ladwa, R., O’Byrne, K., & Kulasinghe, A. (2022) · Current Oncology · doi:10.3390/curroncol29050247 · Cited by 1,353 · see citing works
Hypoxia drives CD39-dependent suppressor function in exhausted T cells to limit antitumor immunity
Vignali, P. D. A., DePeaux, K., Watson, M. J., Ye, C., Ford, B. R., Lontos, K., McGaa, N. K., Scharping, N. E., Menk, A. V., Robson, S. C., et al. (2023) · Nature Immunology · doi:10.1038/s41590-022-01379-9 · Cited by 269 · see citing works
Self-citationMa, S., Zhao, Y., Lee, W. C., Ong, L.-T., Lee, P. L., Jiang, Z., Oguz, G., Niu, Z., Liu, M., Goh, J. Y., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-31764-9 · Cited by 200 · see citing works
- Authors
- Zandberg, D. P., Menk, A. V., Velez, M., Normolle, D., DePeaux, K., Liu, A., Ferris, R. L., & Delgoffe, G. M.
- Affiliations
- UPMC Hillman Cancer Center (US)
- University of Pittsburgh (US)
- Corresponding author
- Delgoffe, Greg M
- Venue
- Journal for ImmunoTherapy of Cancer
- Publisher
- BMJ
- Published
- 2021-05
- Volume
- 9
- Issue
- 5
- Pages
- e002088
- ISSN
- 2051-1426 (ISSN-L)
- PMC
- PMC8126285
- OpenAlex
- W3161451006
- Cited by
- 119
- References
- 22
- Citations by year
- 2026: 9 · 2025: 16 · 2024: 33 · 2023: 35 · 2022: 16 · 2021: 9 · 2013: 1
- FWCI
- 8.55
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal for ImmunoTherapy of Cancer (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Cancer Institute (P30CA047904, P50CA097190)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Otorhinolaryngology › Head and Neck Cancer Studies
- Keywords
- tumor hypoxia, anti-PD-1 resistance, head and neck squamous cell carcinoma, oxidative metabolism, glycolytic metabolism, carbonic anhydrase IX, CD8+ T cell infiltration, regulatory T cells, tumor microenvironment, pimonidazole, predictive biomarkers, immunotherapy response, cancer metabolism
- MeSH terms
- Tumor Hypoxia, Antineoplastic Agents, Immunological, Squamous Cell Carcinoma of Head and Neck, Progression-Free Survival, Immune Checkpoint Inhibitors, Adult, Aged, Aged, 80 and over, Animals, Energy Metabolism, Female, Head and Neck Neoplasms, Humans, Male, Mice, Inbred C57BL, Middle Aged, Oxidation-Reduction, Retrospective Studies, T-Lymphocytes, Signal Transduction, Lymphocytes, Tumor-Infiltrating, Drug Resistance, Neoplasm, Xenograft Model Antitumor Assays, Cell Line, Tumor, Tumor Burden, Mice, Tumor Microenvironment, Programmed Cell Death 1 Receptor
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
