68Ga-FAPI PET imaging monitors response to combined TGF-βR inhibition and immunotherapy in metastatic colorectal cancer

Ke Li; Wei Liu; Hang Yu; Jiwei Chen; Wenxuan Tang; Jianpeng Wang; Ming Qi; Yuyun Sun; Xiaoping Xu; Ji Zhang; Xinxiang Li; Weijian Guo; Xiaoling Li; Shaoli Song; Shuang Tang

doi:10.1172/JCI170490

68Ga-FAPI PET imaging monitors response to combined TGF-βR inhibition and immunotherapy in metastatic colorectal cancer

J Clin Invest. 2024 Jan 4;134(4):e170490. doi: 10.1172/JCI170490.

Authors

Ke Li^{1

2

3

4}, Wei Liu^{1

2

3

4}, Hang Yu^{1

2

3

4}, Jiwei Chen¹, Wenxuan Tang^{1

5}, Jianpeng Wang⁶, Ming Qi^{1

2

3

4}, Yuyun Sun^{1

2

3

4}, Xiaoping Xu^{1

2

3

4}, Ji Zhang^{1

2

3

4}, Xinxiang Li^{4

7

8}, Weijian Guo^{4

9}, Xiaoling Li¹⁰, Shaoli Song^{1

2

3

4}, Shuang Tang^{1

2

3

4}

Affiliations

¹ Cancer Institute, Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, China.
² Center for Biomedical Imaging, Fudan University, Shanghai, China.
³ Shanghai Engineering Research Center of Molecular Imaging Probes, Shanghai, China.
⁴ Department of Oncology and.
⁵ School of Clinical Medicine, Shanghai Medical College, Fudan University, Shanghai, China.
⁶ Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
⁷ Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
⁸ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
⁹ Department of Gastrointestinal Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
¹⁰ Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.

Abstract

BACKGROUNDImproving and predicting tumor response to immunotherapy remains challenging. Combination therapy with a transforming growth factor-β receptor (TGF-βR) inhibitor that targets cancer-associated fibroblasts (CAFs) is promising for the enhancement of efficacy of immunotherapies. However, the effect of this approach in clinical trials is limited, requiring in vivo methods to better assess tumor responses to combination therapy.METHODSWe measured CAFs in vivo using the 68Ga-labeled fibroblast activation protein inhibitor-04 (68Ga-FAPI-04) for PET/CT imaging to guide the combination of TGF-β inhibition and immunotherapy. One hundred thirty-one patients with metastatic colorectal cancer (CRC) underwent 68Ga-FAPI and 18F-fluorodeoxyglucose (18F-FDG) PET/CT imaging. The relationship between uptake of 68Ga-FAPI and tumor immunity was analyzed in patients. Mouse cohorts of metastatic CRC were treated with the TGF-βR inhibitor combined with KN046, which blocks programmed death ligand 1 (PD-L1) and CTLA-4, followed by 68Ga-FAPI and 18F-FDG micro-PET/CT imaging to assess tumor responses.RESULTSPatients with metastatic CRC demonstrated high uptake rates of 68Ga-FAPI, along with suppressive tumor immunity and poor prognosis. The TGF-βR inhibitor enhanced tumor-infiltrating T cells and significantly sensitized metastatic CRC to KN046. 68Ga-FAPI PET/CT imaging accurately monitored the dynamic changes of CAFs and tumor response to combined the TGF-βR inhibitor with immunotherapy.CONCLUSION68Ga-FAPI PET/CT imaging is powerful in assessing tumor immunity and the response to immunotherapy in metastatic CRC. This study supports future clinical application of 68Ga-FAPI PET/CT to guide precise TGF-β inhibition plus immunotherapy in CRC patients, recommending 68Ga-FAPI and 18F-FDG dual PET/CT for CRC management.TRIAL REGISTRATIONCFFSTS Trial, ChiCTR2100053984, Chinese Clinical Trial Registry.FUNDINGNational Natural Science Foundation of China (82072695, 32270767, 82272035, 81972260).

Keywords: Cancer immunotherapy; Colorectal cancer; Diagnostic imaging; Gastroenterology; Oncology.

MeSH terms

Animals
Antibodies, Bispecific*
Colonic Neoplasms*
Fluorodeoxyglucose F18
Humans
Immunotherapy
Mice
Positron Emission Tomography Computed Tomography
Positron-Emission Tomography
Quinolines*
Receptors, Transforming Growth Factor beta
Transforming Growth Factor beta

Substances

Receptors, Transforming Growth Factor beta
68Ga-FAPI
Fluorodeoxyglucose F18
Antibodies, Bispecific
Transforming Growth Factor beta
Quinolines

Grants and funding

This work was supported by the National Key Research and Development Program of China to Tang. S (No. 2021YFA0805500), National Natural Science Foundation of China to Tang. S (82072695, 32270767), Song. S (82272035), and Li. X (81972260).