68Ga-FAPI PET imaging monitors response to combined TGF-βR inhibition and immunotherapy in metastatic colorectal cancer
Ke Li, … , Shaoli Song, Shuang Tang
Ke Li, … , Shaoli Song, Shuang Tang
Published January 4, 2024
Citation Information: J Clin Invest. 2024;134(4):e170490. https://doi.org/10.1172/JCI170490.
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Clinical Research and Public Health Gastroenterology Oncology

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

Abstract

BACKGROUND Improving 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.METHODS We 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.RESULTS Patients 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.CONCLUSION 68Ga-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 REGISTRATION CFFSTS Trial, ChiCTR2100053984, Chinese Clinical Trial Registry.FUNDING National Natural Science Foundation of China (82072695, 32270767, 82272035, 81972260).

Authors

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

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Figure 6

Using 68Ga-FAPI micro-PET/CT and 18F-FDG micro-PET/CT imaging to assess sensitization of colorectal liver metastases to ICB KN046 by TGF-β inhibition.

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Using 68Ga-FAPI micro-PET/CT and 18F-FDG micro-PET/CT imaging to assess ...
(A) Schematic representation of MRI and PET imaging and treatment strategies in mice with MC38 liver metastasis (4 groups, n = 6 per group). Created with BioRender. (B) Representative micro-MRI images of mice with MC38 liver metastasis after the indicated treatments. Yellow arrows indicate tumor lesions. (C) Representative liver images of mice with liver metastasis after the indicated treatments. (D) Liver weights of mice with MC38 liver metastasis after the indicated treatments. (E–G) Proportion of CD8+ T cells, CD8+IFN-γ+ T cells, and CD8+GZMB+ T cells in CD45+ cells in liver metastasis harvested from mice of the 4 groups as measured using flow cytometry. (H) Representative 68Ga-FAPI micro-PET/CT images of mice with liver metastasis after the indicated treatments. B, bladder; K, kidney; T, tumor. (I) Quantified tumor uptake of 68Ga-FAPI in mice with liver metastasis (n = 3 per group). (J) Representative 18F-FDG micro-PET/CT images of mice with liver metastasis after the indicated treatments. (K) Quantified tumor uptake of 18F-FDG in mice with liver metastasis after the indicated treatments (n = 3 per group). (L) IHC staining of FAP-α in tumors of mice with liver metastasis after the indicated treatments. Scale bars: 20 μm. (M) Quantified IHC staining of FAP-α in tumors of mice with liver metastasis after the indicated treatments. All numerical data are presented as mean ± SEM. *P < 0.05, **P < 0.01 by 1-way ANOVA with Dunnett’s correct multiple-comparison test (D–G, I, K, and M).