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FGFR2 promotes expression of PD-L1 in colorectal cancer via JAK/STAT3 signaling pathway

FGFR2 promotes expression of PD-L1 in colorectal cancer via JAK/STAT3 signaling pathway
FGFR2 promotes expression of PD-L1 in colorectal cancer via JAK/STAT3 signaling pathway
Although multidisciplinary treatment is widely applied in colorectal cancer (CRC), the prognosis of patients with advanced CRC remains poor. Immunotherapy blocking of programmed death-1 ligand 1 (PD-L1) is a promising approach. Binding of the transmembrane protein PD-L1 expressed by tumor cells or tumor microenvironment cells to its receptor programmed cell death 1 (PD-1) induces immunosuppressive signals and reduces the proliferation of T cells, which is an important mechanism of tumor immune escape and key issue in immunotherapy. However, the regulation of PDL1 expression is poorly understood in CRC. Fibroblast growth factor receptor 2 (FGFR2) causes the tyrosine kinase domains to initiate a cascade of intracellular signals by binding to fibroblast growth factors (FGFs) and dimerization (pairing of receptors), which is involved in tumorigenesis and progression. Here, we showed that PD-L1 and FGFR2 were frequently overexpressed in CRC and FGFR2 expression was significantly associated with lymph node metastasis, clinical stage, and poor survival. In the present study, PD-L1 expression was positively correlated with FGFR2 expression in CRC. Tumor-derived activated FGFR2 induced PD-L1 expression via the Janus kinase-signal transducer and activator of transcription 3 signaling pathway in human colorectal cancer cells (SW480 and NCI-H716), which induced the apoptosis of Jurkat T cells. FGFR2 also promoted the expression of PD-L1 in xenograft mouse model of colorectal cancer. Our results reveal a novel mechanism of PD-L1 expression in CRC, thus providing theoretical basis for reversing the immune tolerance of FGFR2 overexpression in CRC.
0022-1767
3065-3075
Li, Piao
9efe396b-b30a-4bc1-9735-87f3a99c7ccf
Huang, Tingting
b212400a-4f0e-4e0c-9499-df684d848ddc
Zou, Qi
2550b265-1644-42f4-9033-34c73cfb6d3d
Liu, Dian
bdc6a019-a490-42e9-a51d-1fb75bb7255e
Wang, Yihua
f5044a95-60a7-42d2-87d6-5f1f789e3a7e
Tan, Ximin
b68c343f-8766-42be-937d-a7a9995dde3f
Wei, Yao
5cb9974a-1fe9-4464-b5a0-9c442a10a70a
Qiu, Hong
7b63b219-1982-44be-b05f-9b8062885581
Li, Piao
9efe396b-b30a-4bc1-9735-87f3a99c7ccf
Huang, Tingting
b212400a-4f0e-4e0c-9499-df684d848ddc
Zou, Qi
2550b265-1644-42f4-9033-34c73cfb6d3d
Liu, Dian
bdc6a019-a490-42e9-a51d-1fb75bb7255e
Wang, Yihua
f5044a95-60a7-42d2-87d6-5f1f789e3a7e
Tan, Ximin
b68c343f-8766-42be-937d-a7a9995dde3f
Wei, Yao
5cb9974a-1fe9-4464-b5a0-9c442a10a70a
Qiu, Hong
7b63b219-1982-44be-b05f-9b8062885581

Li, Piao, Huang, Tingting, Zou, Qi, Liu, Dian, Wang, Yihua, Tan, Ximin, Wei, Yao and Qiu, Hong (2019) FGFR2 promotes expression of PD-L1 in colorectal cancer via JAK/STAT3 signaling pathway. The Journal of Immunology, 202 (10), 3065-3075. (doi:10.4049/jimmunol.1801199).

Record type: Article

Abstract

Although multidisciplinary treatment is widely applied in colorectal cancer (CRC), the prognosis of patients with advanced CRC remains poor. Immunotherapy blocking of programmed death-1 ligand 1 (PD-L1) is a promising approach. Binding of the transmembrane protein PD-L1 expressed by tumor cells or tumor microenvironment cells to its receptor programmed cell death 1 (PD-1) induces immunosuppressive signals and reduces the proliferation of T cells, which is an important mechanism of tumor immune escape and key issue in immunotherapy. However, the regulation of PDL1 expression is poorly understood in CRC. Fibroblast growth factor receptor 2 (FGFR2) causes the tyrosine kinase domains to initiate a cascade of intracellular signals by binding to fibroblast growth factors (FGFs) and dimerization (pairing of receptors), which is involved in tumorigenesis and progression. Here, we showed that PD-L1 and FGFR2 were frequently overexpressed in CRC and FGFR2 expression was significantly associated with lymph node metastasis, clinical stage, and poor survival. In the present study, PD-L1 expression was positively correlated with FGFR2 expression in CRC. Tumor-derived activated FGFR2 induced PD-L1 expression via the Janus kinase-signal transducer and activator of transcription 3 signaling pathway in human colorectal cancer cells (SW480 and NCI-H716), which induced the apoptosis of Jurkat T cells. FGFR2 also promoted the expression of PD-L1 in xenograft mouse model of colorectal cancer. Our results reveal a novel mechanism of PD-L1 expression in CRC, thus providing theoretical basis for reversing the immune tolerance of FGFR2 overexpression in CRC.

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Accepted/In Press date: 14 February 2019
e-pub ahead of print date: 12 April 2019
Published date: 15 May 2019

Identifiers

Local EPrints ID: 430165
URI: https://eprints.soton.ac.uk/id/eprint/430165
ISSN: 0022-1767
PURE UUID: e0c0fc29-8b06-4e2e-9045-c9290d157db9
ORCID for Yihua Wang: ORCID iD orcid.org/0000-0001-5561-0648

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Date deposited: 15 Apr 2019 16:30
Last modified: 28 May 2019 00:29

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Contributors

Author: Piao Li
Author: Tingting Huang
Author: Qi Zou
Author: Dian Liu
Author: Yihua Wang ORCID iD
Author: Ximin Tan
Author: Yao Wei
Author: Hong Qiu

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