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18F-fluorodeoxyglucose positron emission tomography correlates with tumor immunometabolic phenotypes in resected lung cancer

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Abstract

Enhanced tumor glycolytic activity is a mechanism by which tumors induce an immunosuppressive environment to resist adoptive T cell therapy; therefore, methods of assessing intratumoral glycolytic activity are of considerable clinical interest. In this study, we characterized the relationships among tumor 18F-fluorodeoxyglucose (FDG) retention, tumor metabolic and immune phenotypes, and survival in patients with resected non-small cell lung cancer (NSCLC). We retrospectively analyzed tumor preoperative positron emission tomography (PET) 18F-FDG uptake in 59 resected NSCLCs and investigated correlations between PET parameters (SUVMax, SUVTotal, SUVMean, TLG), tumor expression of glycolysis- and immune-related genes, and tumor-associated immune cell densities that were quantified by immunohistochemistry. Tumor glycolysis-associated immune gene signatures were analyzed for associations with survival outcomes. We found that each 18F-FDG PET parameter was positively correlated with tumor expression of glycolysis-related genes. Elevated 18F-FDG SUVMax was more discriminatory of glycolysis-associated changes in tumor immune phenotypes than other 18F-FDG PET parameters. Increased SUVMax was associated with multiple immune factors characteristic of an immunosuppressive and poorly immune infiltrated tumor microenvironment, including elevated PD-L1 expression, reduced CD57+ cell density, and increased T cell exhaustion gene signature. Elevated SUVMax identified immune-related transcriptomic signatures that were associated with enhanced tumor glycolytic gene expression and poor clinical outcomes. Our results suggest that 18F-FDG SUVMax has potential value as a noninvasive, clinical indicator of tumor immunometabolic phenotypes in patients with resectable NSCLC and warrants investigation as a potential predictor of therapeutic response to immune-based treatment strategies.

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Abbreviations

18F-FDG:

18F-fluorodeoxyglucose

CI:

Confidence interval

CT:

Computed tomography

DFS:

Disease-free survival

DISTHG:

Downregulated Immune Signature of Tumors with High Glycolysis

FFPE:

Formalin-fixed, paraffin-embedded

HR:

Hazard ratio

ICI:

Immune checkpoint inhibitor

IHC:

Immunohistochemistry

IQR:

Interquartile range

NSCLC:

Non-small cell lung cancer

OS:

Overall survival

PET:

Positron emission tomography

PROSPECT:

Profiling of Resistance Patterns and Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax

SUV:

Standardized uptake value

TAIC:

Tumor-associated immune cell

TLG:

Total lesion glycolysis

UISTHG:

Upregulated Immune Signature of Tumors with High Glycolysis

VOI:

Volume of interest

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Acknowledgements

The authors appreciate the assistance of Mr. Alex Liu with the Division of Information Services, Oncology Care and Research IS at MD Anderson Cancer Center, and Mr. Donald Norwood with the Department of Scientific Publications at MD Anderson Cancer Center for his editorial assistance.

Funding

This work was supported in part by the National Cancer Institute (5 P50 CA070907; P50 CA221703; R01 CA187076; R01 CA184845, P30CA01667), the Cancer Prevention and Research Institute of Texas (RP170401), the American Society of Clinical Oncology 2018 Career Development Award (12895), the Department of Defense (W81XWH-07-1-0306), and the Bob Mayberry Foundation. This work was also supported in part by the Bruton Endowed Chair in Tumor Biology Funds, and the generous philanthropic contributions to the University of Texas MD Anderson Cancer Center Lung Cancer Moon Shot Program, the Khalifa Scholars Program (from Khalifa Bin Zayed Al Nahyan Foundation), the Advanced Scholar Program (from CG Johnson Foundation), and the Physician Scientist Program (from T.J. Martell Foundation).

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Authors and Affiliations

  1. Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Kyle G. Mitchell, Boris Sepesi, Garrett L. Walsh, Ara A. Vaporciyan, Wayne L. Hofstetter & Stephen G. Swisher

  2. Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Behrang Amini, Brett W. Carter & Myrna C. B. Godoy

  3. Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Yunfei Wang, Patrick Hwu & Weiyi Peng

  4. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Edwin R. Parra, Pamela Villalobos, Junya Fujimoto, Humam Kadara & Ignacio I. Wistuba

  5. Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 432, Houston, TX, 77030, USA

    Carmen Behrens, Alexandre Reuben, William N. William Jr., Don L. Gibbons, Ignacio I. Wistuba, John V. Heymach & Tina Cascone

  6. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    J. Jack Lee

  7. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Annikka Weissferdt & Cesar A. Moran

  8. Hospital BP, a Beneficencia Portuguesa de Sao Paulo, Sao Paulo, Brazil

    William N. William Jr.

  9. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Don L. Gibbons

  10. Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Jing Wang

  11. Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    David Piwnica-Worms

  12. Department of Biology and Biochemistry, The University of Houston, 3517 Cullen Blvd., Houston, TX, 77204, USA

    Weiyi Peng

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  1. Kyle G. Mitchell
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  25. Ignacio I. Wistuba
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  27. Weiyi Peng
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Contributions

WP and TC contributed to conception and design. TC, WP, BA, and ERP contributed to development of methodology. TC, WP, BA, KGM, HK, ERP, PV, CB, AR, YW, JW, AW, CAM, and JF contributed to data acquisition. TC, WP, KGM, BA, ERP, PV, CB, AR, YW, AW, JJL, and DPW contributed to analysis and interpretation of data. KGM, BA, BS, MCBG, ERP, PV, HK, CB, AR, AAV, WLH, SGS, WNW, DLG, IIW, PH, JVH, BWC, YW, JW, JJL, DPW, AW, CAM, JF, GLW, DPW, WP, and TC wrote, reviewed, and revised the manuscript. TC, WP, JVH, and IIW contributed to administrative, technical, or material support. WP and TC contributed to study supervision.

Corresponding authors

Correspondence to Weiyi Peng or Tina Cascone.

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Conflict of interest

M.C.B. Godoy has received research funding from Siemens Healthcare. W.N. William has received honoraria/speaker’s fees and/or participated in advisory boards from Roche/Genentech, Bristol-Myers Squibb, Eli Lilly, Merck, AstraZeneca, and Pfizer. D.L. Gibbons has received research funding from AstraZeneca, Janssen, and Takeda and has participated in advisory boards for AstraZeneca and Sanofi. P. Hwu is a consultant and/or has participated in advisory boards for Immatics, Dragonfly, Sanofi, and GlaxoSmithKline. S.G. Swisher has participated in advisory committees for Ethicon and for the Peter MacCallum Cancer Center. B.S. receives consulting fees from Bristol-Myers Squibb. J.V. Heymach has received research support from AstraZeneca, Bayer, GlaxoSmithKline, and Spectrum; participated in advisory committees for AstraZeneca, Boehringer Ingelheim, Exelixis, Genentech, GlaxoSmithKline, Guardant Health, Hengrui, Lilly, Novartis, Specrtum, EMD Serono, and Synta; and received royalties and/or licensing fees from Spectrum. P. Hwu and W. Peng have received research funding in the form of grants to MD Anderson Cancer Center from GlaxoSmith Kline. T. Cascone has received speaker’s fees from the Society for Immunotherapy of Cancer and Bristol-Myers Squibb; receives consulting/advisory role fees from MedImmune, Bristol-Myers Squibb and EMD Serono, and research funding to MD Anderson Cancer Center from Boehringer Ingelheim, MedImmune and Bristol-Myers Squibb. No potential conflicts of interest are disclosed by the other authors.

Ethical approval

The study was approved by The University of Texas MD Anderson Cancer Center's Institutional Review Board (PROSPECT—LAB07-0233).

Human and animal rights

All human studies were conducted in accordance with the Declaration of Helsinki.

Informed consent

Informed consent was obtained from all study participants.

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Mitchell, K.G., Amini, B., Wang, Y. et al. 18F-fluorodeoxyglucose positron emission tomography correlates with tumor immunometabolic phenotypes in resected lung cancer. Cancer Immunol Immunother 69, 1519–1534 (2020). https://doi.org/10.1007/s00262-020-02560-5

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