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

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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ORCID for Yihua Wang: orcid.org/0000-0001-5561-0648

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