IL-17D improves cytotoxic function of CD93+CTL in lung tumor micro-environment and promotion of Platycodon grandiflorum
Objective:To investigate mechanisms of IL-17D on cytotoxic function of CD93+CTL in lung tumor microenviron-ment(TME)and promotion of Platycodon grandiflorum(PG).Methods:Lung of B16 melanoma model mice and control mice were treated with PG or IL-17D,and lung tumor clone formation was observed.IL-17D expression change in lung was detected by single cell sequencing,immunofluorescence staining and flow cytometry.Single cell sequencing and flow cytometry were used to detect CD93+CTL content,cytotoxic phenotype and functional factors changes,including CD107a,perforin,granzyme B,chemokine CCL2,CXCL9 and their ligand CCR2 and CXCR3.Western blot and RT-PCR were used to detect effect of Platycodonopsis saponin D on IL-17D and its transcriptional regulator NRF2 expressions in EL4 cells.Results:Pulmonary CD93+CTL highly expressed cytotoxic effectors such as perforin and CD107a and chemokine receptors CXCR3 and CCR2 than CD93-CTL,while there was no significant difference in secretion of granzyme B.In mouse lung tumor model,pulmonary IL-17D and CD93+CTL were significantly decreased(P<0.001);in tumor-bearing mice after IL-17D backfill assay,or after 10 days of treatment with PG,proportion and absolute number of IL-17D and CD93+CTL in lungs were significantly increased(P<0.05),and tumor clones were significantly reduced;meanwhile,tumor-local expressions of cytokines CCL2,CXCL9,which are related to recruitment and function of CD93+CTL,and IL-17D were significantly upregulated.Up-regulation of IL-17D and its transcriptional regulator NRF2 by PG was verified in vitro experiments on EL4 cell line by PD.Conclusion:Traditional Chinese medicine PG and its extracts can up-regulate expression of IL-17D in lungs,improve infiltration and cytotoxic function of CD93+CTL and antagonize malignant progression of lung tumors,this is an important phar-macological mechanism of PG in improving immune TME of tumors in lung.
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