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Cancer Immunology Research
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Oxidized Lipoproteins Promote Resistance to Cancer Immunotherapy Independent of Patient Obesity

Niloufar Khojandi, Lindsey M. Kuehm, Alexander Piening, Maureen J. Donlin, Eddy C. Hsueh, Theresa L. Schwartz, Kaitlin Farrell, John M. Richart, Elizabeth Geerling, Amelia K. Pinto, Sarah L. George, Carolyn J. Albert, David A. Ford, Xiufen Chen, Justin Kline and Ryan M. Teague
Niloufar Khojandi
1Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri.
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Lindsey M. Kuehm
1Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri.
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Alexander Piening
1Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri.
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  • ORCID record for Alexander Piening
Maureen J. Donlin
2Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, Missouri.
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Eddy C. Hsueh
3Department of Surgery, Saint Louis University School of Medicine, St. Louis, Missouri.
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Theresa L. Schwartz
3Department of Surgery, Saint Louis University School of Medicine, St. Louis, Missouri.
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Kaitlin Farrell
3Department of Surgery, Saint Louis University School of Medicine, St. Louis, Missouri.
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John M. Richart
4Department of Internal Medicine, Division of Hematology and Oncology, Saint Louis University School of Medicine, St. Louis, Missouri.
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  • ORCID record for John M. Richart
Elizabeth Geerling
1Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri.
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Amelia K. Pinto
1Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri.
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Sarah L. George
5Department of Internal Medicine, Division of Infectious Diseases, Allergy and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri.
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Carolyn J. Albert
2Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, Missouri.
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David A. Ford
2Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, Missouri.
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Xiufen Chen
6Department of Medicine, University of Chicago, Chicago, Illinois.
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Justin Kline
6Department of Medicine, University of Chicago, Chicago, Illinois.
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Ryan M. Teague
1Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri.
7Alvin J. Siteman National Cancer Institute Comprehensive Cancer Center, St. Louis, Missouri.
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  • For correspondence: ryan.teague@health.slu.edu
DOI: 10.1158/2326-6066.CIR-20-0358 Published February 2021
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Abstract

Antitumor immunity is impaired in obese mice. Mechanistic insight into this observation remains sparse and whether it is recapitulated in patients with cancer is unclear because clinical studies have produced conflicting and controversial findings. We addressed this by analyzing data from patients with a diverse array of cancer types. We found that survival after immunotherapy was not accurately predicted by body mass index or serum leptin concentrations. However, oxidized low-density lipoprotein (ox-LDL) in serum was identified as a suppressor of T-cell function and a driver of tumor cytoprotection mediated by heme oxygenase-1 (HO-1). Analysis of a human melanoma gene expression database showed a clear association between higher HMOX1 (HO-1) expression and reduced progression-free survival. Our in vivo experiments using mouse models of both melanoma and breast cancer revealed HO-1 as a mechanism of resistance to anti-PD1 immunotherapy but also exposed HO-1 as a vulnerability that could be exploited therapeutically using a small-molecule inhibitor. In conclusion, our clinical data have implicated serum ox-LDL as a mediator of therapeutic resistance in patients with cancer, operating as a double-edged sword that both suppressed T-cell immunity and simultaneously induced HO-1–mediated tumor cell protection. Our studies also highlight the therapeutic potential of targeting HO-1 during immunotherapy, encouraging further translational development of this combination approach.

See article by Kuehm et al., p. 227

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Cancer Immunol Res 2021;9:214–26

  • Received April 29, 2020.
  • Revision received October 7, 2020.
  • Accepted December 3, 2020.
  • Published first December 10, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Immunology Research: 9 (2)
February 2021
Volume 9, Issue 2
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Oxidized Lipoproteins Promote Resistance to Cancer Immunotherapy Independent of Patient Obesity
Niloufar Khojandi, Lindsey M. Kuehm, Alexander Piening, Maureen J. Donlin, Eddy C. Hsueh, Theresa L. Schwartz, Kaitlin Farrell, John M. Richart, Elizabeth Geerling, Amelia K. Pinto, Sarah L. George, Carolyn J. Albert, David A. Ford, Xiufen Chen, Justin Kline and Ryan M. Teague
Cancer Immunol Res February 1 2021 (9) (2) 214-226; DOI: 10.1158/2326-6066.CIR-20-0358

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Oxidized Lipoproteins Promote Resistance to Cancer Immunotherapy Independent of Patient Obesity
Niloufar Khojandi, Lindsey M. Kuehm, Alexander Piening, Maureen J. Donlin, Eddy C. Hsueh, Theresa L. Schwartz, Kaitlin Farrell, John M. Richart, Elizabeth Geerling, Amelia K. Pinto, Sarah L. George, Carolyn J. Albert, David A. Ford, Xiufen Chen, Justin Kline and Ryan M. Teague
Cancer Immunol Res February 1 2021 (9) (2) 214-226; DOI: 10.1158/2326-6066.CIR-20-0358
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