Evaluating the immunologically "cold" tumor microenvironment after treatment with immune checkpoint inhibitors utilizing PET imaging of CD4 + and CD8 + T cells in breast cancer mouse models.

Autor: Lu Y; Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.; Graduate Biomedical Sciences, University of Alabama at Birmingham, Birmingham, AL, 35233, USA., Houson HA; Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA., Gallegos CA; Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.; Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL, 35233, USA., Mascioni A; ImaginAb, Inc, Inglewood, CA, 90301, USA., Jia F; ImaginAb, Inc, Inglewood, CA, 90301, USA., Aivazian A; ImaginAb, Inc, Inglewood, CA, 90301, USA., Song PN; Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.; Graduate Biomedical Sciences, University of Alabama at Birmingham, Birmingham, AL, 35233, USA., Lynch SE; Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.; Graduate Biomedical Sciences, University of Alabama at Birmingham, Birmingham, AL, 35233, USA., Napier TS; Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.; Graduate Biomedical Sciences, University of Alabama at Birmingham, Birmingham, AL, 35233, USA., Mansur A; Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.; Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL, 35233, USA., Larimer BM; Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, 35233, USA., Lapi SE; Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, 35233, USA.; Department of Chemistry, University of Alabama at Birmingham, Birmingham, AL, 35233, USA., Hanker AB; Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, 75390, USA., Sorace AG; Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, 35233, USA. asorace@uabmc.edu.; Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL, 35233, USA. asorace@uabmc.edu.; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, 35233, USA. asorace@uabmc.edu.; Departments of Radiology and Biomedical Engineering, O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Small Animal Imaging Facility, 1670 University Blvd, Birmingham, USA. asorace@uabmc.edu.
Jazyk: angličtina
Zdroj: Breast cancer research : BCR [Breast Cancer Res] 2024 Jun 25; Vol. 26 (1), pp. 104. Date of Electronic Publication: 2024 Jun 25.
DOI: 10.1186/s13058-024-01844-3
Abstrakt: Background: Immune-positron emission tomography (PET) imaging with tracers that target CD8 and granzyme B has shown promise in predicting the therapeutic response following immune checkpoint blockade (ICB) in immunologically "hot" tumors. However, immune dynamics in the low T-cell infiltrating "cold" tumor immune microenvironment during ICB remain poorly understood. This study uses molecular imaging to evaluate changes in CD4 + T cells and CD8 + T cells during ICB in breast cancer models and examines biomarkers of response.
Methods: [ 89 Zr]Zr-DFO-CD4 and [ 89 Zr]Zr-DFO-CD8 radiotracers were used to quantify changes in intratumoral and splenic CD4 T cells and CD8 T cells in response to ICB treatment in 4T1 and MMTV-HER2 mouse models, which represent immunologically "cold" tumors. A correlation between PET quantification metrics and long-term anti-tumor response was observed. Further biological validation was obtained by autoradiography and immunofluorescence.
Results: Following ICB treatment, an increase in the CD8-specific PET signal was observed within 6 days, and an increase in the CD4-specific PET signal was observed within 2 days in tumors that eventually responded to immunotherapy, while no significant differences in CD4 or CD8 were found at the baseline of treatment that differentiated responders from nonresponders. Furthermore, mice whose tumors responded to ICB had a lower CD8 PET signal in the spleen and a higher CD4 PET signal in the spleen compared to non-responders. Intratumoral spatial heterogeneity of the CD8 and CD4-specific PET signals was lower in responders compared to non-responders. Finally, PET imaging, autoradiography, and immunofluorescence signals were correlated when comparing in vivo imaging to ex vivo validations.
Conclusions: CD4- and CD8-specific immuno-PET imaging can be used to characterize the in vivo distribution of CD4 + and CD8 + T cells in response to immune checkpoint blockade. Imaging metrics that describe the overall levels and distribution of CD8 + T cells and CD4 + T cells can provide insight into immunological alterations, predict biomarkers of response to immunotherapy, and guide clinical decision-making in those tumors where the kinetics of the response differ.
(© 2024. The Author(s).)
Databáze: MEDLINE
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