Visualization of tumor-immune interaction: Target-specific imaging of S100A8/A9 reveals pre-metastatic niche establishment

Michel Eisenblaetter; Fabian Flores-Borja; Jae Jin Lee; Christina  Wefers; Hannah Smith; Rebekka Hueting; Margaret Susan Cooper; Philip J Blower; Dominic Patel; Manuel Rodriguez-Justo; Hanna Milewicz; Thomas Vogl; Johannes Roth; Andrew Tutt; Tobias Schaeffter; Tony Ng

doi:10.7150/thno.17138

Visualization of tumor-immune interaction: Target-specific imaging of S100A8/A9 reveals pre-metastatic niche establishment

Michel Eisenblaetter^*, Fabian Flores-Borja, Jae Jin Lee, Christina Wefers, Hannah Smith, Rebekka Hueting, Margaret Susan Cooper, Philip J Blower, Dominic Patel, Manuel Rodriguez-Justo, Hanna Milewicz, Thomas Vogl, Johannes Roth, Andrew Tutt, Tobias Schaeffter, Tony Ng

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Background: Systemic cancer spread is preceded by the establishment of a permissive microenvironment in the target tissue of metastasis - the premetastatic niche. As crucial players in establishment of the pre-metastatic niche, myeloid derived suppressor cells (MDSC) release S100A8/A9, an exosomal protein that contributes to metastasis, angiogenesis, and immune suppression. We report the application of antibody-based single-photon emission computed tomography (SPECT) for detection of S100A8/A9 in vivo as an imaging marker for pre-metastatic tissue priming.

Methods: A syngeneic model system for invasive breast cancer with (4T1.2) or without (67NR) the tendency to form lung metastasis was established in BALB/c mice. A SPECT-probe has been generated and tested for visualization of S100A9 release. Tumor-associated changes in numbers and fuction of immune cells in pre-metastatic tissue were evaluated by flow cytometry and confocal microscopy.

Results: S100A8/A9 imaging reflected MDSC abundance and the establishment of an immunosuppressive environment in pre-metastatic lung tissue (activity 4T1.2 vs. healthy control: 0.95 vs. 0.45 %ID; p < 0 .001). The S100A8/A9 imaging signal in the pre-metastatic lung correlated with the subsequent metastatic tumor burden in the same organ (r²=0.788; p < 0.0001). CCL2 blockade and the consecutive inhibition of premetastatic niche establishment was clearly depicted by S100A9-SPECT (lung activity untreated vs. treated: 2 vs, 1.4 %ID).

Conclusion: We report S100A8/A9 as a potent imaging biomarker for tumor-mediated immune remodeling with potential applications in basic research and clinical oncology.

Original language	English
Pages (from-to)	2392-2401
Journal	Theranostics
Volume	7
Issue number	9
Early online date	15 Jun 2017
DOIs	https://doi.org/10.7150/thno.17138 https://doi.org/10.7150/thno.17138
Publication status	Published - 31 Aug 2017

Keywords

Imaging
MDSC
Premetastatic niche
Tumour immunology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Visualization of tumor-immune_EISENBLAETTER_Publishedonline15June2017_GOLD VoR (CC BY)Final published version, 1.96 MBLicence: CC BY

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Eisenblaetter, M., Flores-Borja, F., Lee, J. J., Wefers, C., Smith, H., Hueting, R., Cooper, M. S., Blower, P. J., Patel, D., Rodriguez-Justo, M., Milewicz, H., Vogl, T., Roth, J., Tutt, A., Schaeffter, T., & Ng, T. (2017). Visualization of tumor-immune interaction: Target-specific imaging of S100A8/A9 reveals pre-metastatic niche establishment. Theranostics, 7(9), 2392-2401. https://doi.org/10.7150/thno.17138, https://doi.org/10.7150/thno.17138

@article{394ced5c6aa4417b9d8b329e3e089a3a,

title = "Visualization of tumor-immune interaction: Target-specific imaging of S100A8/A9 reveals pre-metastatic niche establishment",

abstract = "Background: Systemic cancer spread is preceded by the establishment of a permissive microenvironment in the target tissue of metastasis - the premetastatic niche. As crucial players in establishment of the pre-metastatic niche, myeloid derived suppressor cells (MDSC) release S100A8/A9, an exosomal protein that contributes to metastasis, angiogenesis, and immune suppression. We report the application of antibody-based single-photon emission computed tomography (SPECT) for detection of S100A8/A9 in vivo as an imaging marker for pre-metastatic tissue priming. Methods: A syngeneic model system for invasive breast cancer with (4T1.2) or without (67NR) the tendency to form lung metastasis was established in BALB/c mice. A SPECT-probe has been generated and tested for visualization of S100A9 release. Tumor-associated changes in numbers and fuction of immune cells in pre-metastatic tissue were evaluated by flow cytometry and confocal microscopy. Results: S100A8/A9 imaging reflected MDSC abundance and the establishment of an immunosuppressive environment in pre-metastatic lung tissue (activity 4T1.2 vs. healthy control: 0.95 vs. 0.45 %ID; p < 0 .001). The S100A8/A9 imaging signal in the pre-metastatic lung correlated with the subsequent metastatic tumor burden in the same organ (r2=0.788; p < 0.0001). CCL2 blockade and the consecutive inhibition of premetastatic niche establishment was clearly depicted by S100A9-SPECT (lung activity untreated vs. treated: 2 vs, 1.4 %ID). Conclusion: We report S100A8/A9 as a potent imaging biomarker for tumor-mediated immune remodeling with potential applications in basic research and clinical oncology.",

keywords = "Imaging, MDSC, Premetastatic niche, Tumour immunology",

author = "Michel Eisenblaetter and Fabian Flores-Borja and Lee, {Jae Jin} and Christina Wefers and Hannah Smith and Rebekka Hueting and Cooper, {Margaret Susan} and Blower, {Philip J} and Dominic Patel and Manuel Rodriguez-Justo and Hanna Milewicz and Thomas Vogl and Johannes Roth and Andrew Tutt and Tobias Schaeffter and Tony Ng",

year = "2017",

month = aug,

day = "31",

doi = "10.7150/thno.17138",

language = "English",

volume = "7",

pages = "2392--2401",

journal = "Theranostics",

issn = "1838-7640",

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number = "9",

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Eisenblaetter, M , Flores-Borja, F, Lee, JJ, Wefers, C, Smith, H, Hueting, R , Cooper, MS , Blower, PJ, Patel, D, Rodriguez-Justo, M, Milewicz, H, Vogl, T, Roth, J, Tutt, A , Schaeffter, T & Ng, T 2017, 'Visualization of tumor-immune interaction: Target-specific imaging of S100A8/A9 reveals pre-metastatic niche establishment', Theranostics, vol. 7, no. 9, pp. 2392-2401. https://doi.org/10.7150/thno.17138, https://doi.org/10.7150/thno.17138

TY - JOUR

T1 - Visualization of tumor-immune interaction

T2 - Target-specific imaging of S100A8/A9 reveals pre-metastatic niche establishment

AU - Eisenblaetter, Michel

AU - Flores-Borja, Fabian

AU - Lee, Jae Jin

AU - Wefers, Christina

AU - Smith, Hannah

AU - Hueting, Rebekka

AU - Cooper, Margaret Susan

AU - Blower, Philip J

AU - Patel, Dominic

AU - Rodriguez-Justo, Manuel

AU - Milewicz, Hanna

AU - Vogl, Thomas

AU - Roth, Johannes

AU - Tutt, Andrew

AU - Schaeffter, Tobias

AU - Ng, Tony

PY - 2017/8/31

Y1 - 2017/8/31

N2 - Background: Systemic cancer spread is preceded by the establishment of a permissive microenvironment in the target tissue of metastasis - the premetastatic niche. As crucial players in establishment of the pre-metastatic niche, myeloid derived suppressor cells (MDSC) release S100A8/A9, an exosomal protein that contributes to metastasis, angiogenesis, and immune suppression. We report the application of antibody-based single-photon emission computed tomography (SPECT) for detection of S100A8/A9 in vivo as an imaging marker for pre-metastatic tissue priming. Methods: A syngeneic model system for invasive breast cancer with (4T1.2) or without (67NR) the tendency to form lung metastasis was established in BALB/c mice. A SPECT-probe has been generated and tested for visualization of S100A9 release. Tumor-associated changes in numbers and fuction of immune cells in pre-metastatic tissue were evaluated by flow cytometry and confocal microscopy. Results: S100A8/A9 imaging reflected MDSC abundance and the establishment of an immunosuppressive environment in pre-metastatic lung tissue (activity 4T1.2 vs. healthy control: 0.95 vs. 0.45 %ID; p < 0 .001). The S100A8/A9 imaging signal in the pre-metastatic lung correlated with the subsequent metastatic tumor burden in the same organ (r2=0.788; p < 0.0001). CCL2 blockade and the consecutive inhibition of premetastatic niche establishment was clearly depicted by S100A9-SPECT (lung activity untreated vs. treated: 2 vs, 1.4 %ID). Conclusion: We report S100A8/A9 as a potent imaging biomarker for tumor-mediated immune remodeling with potential applications in basic research and clinical oncology.

AB - Background: Systemic cancer spread is preceded by the establishment of a permissive microenvironment in the target tissue of metastasis - the premetastatic niche. As crucial players in establishment of the pre-metastatic niche, myeloid derived suppressor cells (MDSC) release S100A8/A9, an exosomal protein that contributes to metastasis, angiogenesis, and immune suppression. We report the application of antibody-based single-photon emission computed tomography (SPECT) for detection of S100A8/A9 in vivo as an imaging marker for pre-metastatic tissue priming. Methods: A syngeneic model system for invasive breast cancer with (4T1.2) or without (67NR) the tendency to form lung metastasis was established in BALB/c mice. A SPECT-probe has been generated and tested for visualization of S100A9 release. Tumor-associated changes in numbers and fuction of immune cells in pre-metastatic tissue were evaluated by flow cytometry and confocal microscopy. Results: S100A8/A9 imaging reflected MDSC abundance and the establishment of an immunosuppressive environment in pre-metastatic lung tissue (activity 4T1.2 vs. healthy control: 0.95 vs. 0.45 %ID; p < 0 .001). The S100A8/A9 imaging signal in the pre-metastatic lung correlated with the subsequent metastatic tumor burden in the same organ (r2=0.788; p < 0.0001). CCL2 blockade and the consecutive inhibition of premetastatic niche establishment was clearly depicted by S100A9-SPECT (lung activity untreated vs. treated: 2 vs, 1.4 %ID). Conclusion: We report S100A8/A9 as a potent imaging biomarker for tumor-mediated immune remodeling with potential applications in basic research and clinical oncology.

KW - Imaging

KW - MDSC

KW - Premetastatic niche

KW - Tumour immunology

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U2 - 10.7150/thno.17138

DO - 10.7150/thno.17138

M3 - Article

AN - SCOPUS:85021251016

SN - 1838-7640

VL - 7

SP - 2392

EP - 2401

JO - Theranostics

JF - Theranostics

IS - 9

ER -

Visualization of tumor-immune interaction: Target-specific imaging of S100A8/A9 reveals pre-metastatic niche establishment

Abstract

Keywords

UN SDGs

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