Multiparametric chemical exchange saturation transfer MRI detects metabolic changes in breast cancer following immunotherapy

Emily Hoffmann; Daniel Schache; Carsten Höltke; Jens Soltwisch; Stephan Niland; Tobias Krähling; Klaus Bergander; Martin Grewer; Christiane Geyer; Linda Groeneweg; Johannes A Eble; Thomas Vogl; Johannes Roth; Walter Heindel; Bastian Maus; Anne Helfen; Cornelius Faber; Moritz Wildgruber; Mirjam Gerwing; Verena Hoerr

doi:10.1186/s12967-023-04451-6

Multiparametric chemical exchange saturation transfer MRI detects metabolic changes in breast cancer following immunotherapy

J Transl Med. 2023 Aug 28;21(1):577. doi: 10.1186/s12967-023-04451-6.

Authors

Emily Hoffmann¹, Daniel Schache², Carsten Höltke², Jens Soltwisch³, Stephan Niland⁴, Tobias Krähling², Klaus Bergander⁵, Martin Grewer², Christiane Geyer², Linda Groeneweg⁶, Johannes A Eble⁴, Thomas Vogl⁶, Johannes Roth⁶, Walter Heindel², Bastian Maus², Anne Helfen², Cornelius Faber², Moritz Wildgruber^{2

7}, Mirjam Gerwing^#², Verena Hoerr^{2

8}

Affiliations

¹ Clinic of Radiology, University of Münster, Münster, Germany. emily.hoffmann@ukmuenster.de.
² Clinic of Radiology, University of Münster, Münster, Germany.
³ Institute of Hygiene, University of Münster, Münster, Germany.
⁴ Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Münster, Germany.
⁵ Institute of Organic Chemistry, University of Münster, Münster, Germany.
⁶ Institute of Immunology, University of Münster, Münster, Germany.
⁷ Department of Radiology, University Hospital, LMU Munich, Munich, Germany.
⁸ Heart Center Bonn, Department of Internal Medicine II, University Hospital Bonn, Bonn, Germany.

^# Contributed equally.

Abstract

Background: With metabolic alterations of the tumor microenvironment (TME) contributing to cancer progression, metastatic spread and response to targeted therapies, non-invasive and repetitive imaging of tumor metabolism is of major importance. The purpose of this study was to investigate whether multiparametric chemical exchange saturation transfer magnetic resonance imaging (CEST-MRI) allows to detect differences in the metabolic profiles of the TME in murine breast cancer models with divergent degrees of malignancy and to assess their response to immunotherapy.

Methods: Tumor characteristics of highly malignant 4T1 and low malignant 67NR murine breast cancer models were investigated, and their changes during tumor progression and immune checkpoint inhibitor (ICI) treatment were evaluated. For simultaneous analysis of different metabolites, multiparametric CEST-MRI with calculation of asymmetric magnetization transfer ratio (MTR_asym) at 1.2 to 2.0 ppm for glucose-weighted, 2.0 ppm for creatine-weighted and 3.2 to 3.6 ppm for amide proton transfer- (APT-) weighted CEST contrast was conducted. Ex vivo validation of MRI results was achieved by ¹H nuclear magnetic resonance spectroscopy, matrix-assisted laser desorption/ionization mass spectrometry imaging with laser postionization and immunohistochemistry.

Results: During tumor progression, the two tumor models showed divergent trends for all examined CEST contrasts: While glucose- and APT-weighted CEST contrast decreased and creatine-weighted CEST contrast increased over time in the 4T1 model, 67NR tumors exhibited increased glucose- and APT-weighted CEST contrast during disease progression, accompanied by decreased creatine-weighted CEST contrast. Already three days after treatment initiation, CEST contrasts captured response to ICI therapy in both tumor models.

Conclusion: Multiparametric CEST-MRI enables non-invasive assessment of metabolic signatures of the TME, allowing both for estimation of the degree of tumor malignancy and for assessment of early response to immune checkpoint inhibition.

Keywords: CEST; Immune checkpoint inhibition; MRI; Metabolism; Tumor malignancy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amides
Animals
Creatine*
Glucose
Immune Checkpoint Inhibitors
Immunotherapy
Magnetic Resonance Imaging
Mice
Neoplasms*

Substances

Creatine
Amides
Glucose
Immune Checkpoint Inhibitors