Hyperresponsiveness to interferon gamma exposure as a response mechanism to anti-PD-1 therapy in microsatellite instability colorectal cancer
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Colorectal cancer (CRC) with high-level microsatellite instability (MSI-H) tends to be associated with a better response to programmed death receptor-1 (PD-1) blockade than does microsatellite stable CRC. However, emerging evidence makes the use of programmed death ligand-1 (PD-L1) as a biomarker problematic. Here, we sought to characterize the interactions between PD-L1 expression and the response to PD-1 blockade therapy in BALB/c mice with a subcutaneous tumor challenge. We further focused on interferon gamma (IFNγ)-induced PD-L1 expression in an in vitro setting to evaluate the responsiveness to IFNγ exposure and the specific signaling of PD-1 in HCT116 and SW480 cell lines. In this study, enhanced PD-L1 expression increased survival in CT26 cells, and PD-1 blockade increased the CTL profile and apoptotic cells in mice with CRC. Our in vitro findings showed that PD-L1 expression was significantly upregulated by a low-dose IFNγ treatment, and the MSI-H cell line might exhibit hyperresponsiveness to IFNγ exposure partly through the JAK–STAT pathway. These results suggest that intrinsic PD-L1 in cooperation with extrinsic IFNγ exposure in CRC may be more responsive to anti-PD-1 therapy, mainly through the CTL profile in the tumor microenvironment.
KeywordsColorectal cancer Microsatellite instability IFNγ PD-L1 CTL
Cytotoxic T lymphocyte
Epidermal growth factor receptor
Hematoxylin and eosin
Janus kinase/signal transducer and activator of transcription 3
Mitogen-activated protein kinase
High-level microsatellite instability
Programmed death ligand-1
Phosphatidylinositol 3 kinase/protein kinase B
Phosphatase and tensin homology deleted on chromosome 10
Reverse-transcription quantitative polymerase chain reactions
TdT-mediated dUTP nick-end labeling
We would like to thank Xiaojin Li (Central laboratory, the second hospital of Yunnan Province) for his technical assistance in flow cytometry.
Conceived and designed the experiments: WY and JD. Performed the experiments: WY, CT, XS, HJ and HH. Analyzed the data: WY and JD. Contributed reagents/animals: DD, HJ and RN. Wrote the paper: WY and JD.
This study was partially supported by the Association Foundation Program of Yunnan Provincial Science and Technology Department and Kunming Medical University (Grant number: 2017FE468(-228)), by the Foundation of Yunnan Medical Science and Technology (Grant number: 2016NS124), and by the National Natural Science Foundation of China (Grant number: 81660472).
Compliance with ethical standards
Conflict of interest
The authors declare no conflicts of interest.
Ethical approval and ethical standards
The animal study was approved by the Animal Experimental Ethical Committee of Kunming Medical University (date of approval: June 2017). The experimental mice used in this study were obtained from the Laboratory Animal Center of Kunming Medical University. All experimental procedures were conducted according to the protocols approved by the National Institute of Health’s Guidelines for the Care and Use of Laboratory Animals. This article does not contain any studies with human participants performed by any of the authors.
Cell line authentication
Human CRC cell lines HCT116 and SW480 were obtained from the Institute of Zoology, Chinese Academy of Sciences (Kunming, China), and rat CRC CT26 cells were purchased from the Cell Bank of the Chinese Academy of Sciences (Shanghai, China). Cell Bank, Type Culture Collection, Chinese Academy of Sciences (CBTCCCAS) can provide the Certificate of STR Analysis.