Dual inhibition of TGFβ signaling and CSF1/CSF1R reprograms tumor-infiltrating macrophages and improves response to chemotherapy via suppressing PD-L1

  • Cancer Lett. 2022 Sep 1;543:215795. doi: 10.1016/j.canlet.2022.215795.
Tsung-Wei Chen  1 ,  Wei-Ze Hung  2 ,  Shu-Fen Chiang  3 ,  William Tzu-Liang Chen  4 ,  Tao-Wei Ke  5 ,  Ji-An Liang  6 ,  Chih-Yang Huang  7 ,  Pei-Chen Yang  2 ,  Kevin Chih-Yang Huang  8 ,  K S Clifford Chao  9
Affiliations
  • 1. Graduate Institute of Biomedical Science, China Medical University, Taichung, 40402, Taiwan; Department of Pathology, Asia University Hospital, Asia University, Taichung, 41354, Taiwan.
  • 2. Proton Therapy and Science Center, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan.
  • 3. Lab of Precision Medicine, Feng-Yuan Hospital, Ministry of Health and Welfare, Taichung, 42055, Taiwan.
  • 4. Department of Colorectal Surgery, China Medical University HsinChu Hospital, China Medical University, HsinChu, 302, Taiwan; Department of Colorectal Surgery, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan; Department of Surgery, School of Medicine, China Medical University, Taichung, 40402, Taiwan.
  • 5. Department of Colorectal Surgery, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan; School of Chinese Medicine & Graduate Institute of Chinese Medicine, China Medical University, Taichung, 40402, Taiwan.
  • 6. Department of Radiation Oncology, China Medical University Hospital, China Medical University, Taichung, Taiwan; Department of Radiotherapy, School of Medicine, China Medical University, Taichung, 40402, Taiwan.
  • 7. Graduate Institute of Biomedical Science, China Medical University, Taichung, 40402, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan; Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan; Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien, 970, Taiwan; Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, 97004, Taiwan.
  • 8. Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung, 40402, Taiwan; Translation Research Core, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan. Electronic address: [email protected].
  • 9. Graduate Institute of Biomedical Science, China Medical University, Taichung, 40402, Taiwan; Proton Therapy and Science Center, China Medical University Hospital, China Medical University, Taichung, 40402, Taiwan; Department of Radiation Oncology, China Medical University Hospital, China Medical University, Taichung, Taiwan. Electronic address: [email protected].
PMID: 35718267 DOI: 10.1016/j.canlet.2022.215795
Abstract

TGFβ contributes to chemoresistance in advanced colorectal Cancer (CRC) via diverse immune-microenvironment mechanisms. Here, we found that Cancer cell autonomous TGFβ directly triggered tumor programmed cell death 1 ligand 1 (PD-L1) upregulation, resulting in resistance to chemotherapy. Inhibition of tumor PD-L1 expression sensitized Cancer cells to chemotherapy, reduced lung metastasis and increased the influx of CD8+ T cells. However, chemorefractory Cancer cell-derived CSF1 recruited TAMs for TGFβ-mediated PD-L1 upregulation via a vicious cycle. High infiltration of macrophages was clinically correlated with the status of tumor PD-L1 after chemotherapy treatment in CRC patients. We found that depletion of immunosuppressive CSF1R+ TAM infiltration and blockade of the TGFβ receptor resulted in an increased influx of cytotoxic CD8+ T and effector memory CD8+ cells, a reduction in regulatory T cells, and a synergistic inhibition of tumor growth when combined with chemotherapy. These findings show that CSF1R+ TAMs and TGFβ are the dominant components that regulate PD-L1 expression within the immunosuppressive tumor microenvironment, providing a therapeutic strategy for advanced CRC patients.

Keywords
CRC; CSF1R; PD-L1; TAMs; TGF.
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