Cisplatin Inhibits Bladder Cancer Proliferation Through cGAS-STING Pathway.
Cisplatin is a commonly used adjuvant chemotherapy for advanced bladder cancer, but its immune related mechanism is still unclear. Exploration the immune effects of cisplatin in bladder cancer would complement the comprehensive mechanism of cisplatin and provide the basis for combination therapy of cisplatin and immunotherapy in bladder cancer.
We confirmed the immune effects of cisplatin on T24 and TCCSUP bladder cancer cell lines in vitro and exploration the important function of these immune effects in bladder cancer microenvironment in mice tumor model.
We found cisplatin induced immune response in bladder cancer by RNA sequencing, and validated cGAS-STING signal was deeply involved in this response. Cisplatin induced cGAS-STING signal inhibited the proliferation of bladder cancer and increased the infiltration percentages of CD8 + T cells and dendritic cells in transplantation mice tumor model. Accumulation of dsDNA and the release of chromatin bound cGAS are important to activate downstream STING.
Our findings indicated a cisplatin related immune effects in bladder cancer, cisplatin combined with immunotherapy might have a synergistic effect for bladder cancer therapy.
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Figure S1. Expression of STING did not affect proliferation of T24 and TCCSUP cell lines in vitro. (A) Western blotting of the polymer state of STING, γ-H2A.X and GAPDH in T24 cell lines treated with 2 μg/ml cisplatin for 0 h, 4 h, 8 h, 12 h, 20 h, 28 h. GAPDH was used as the control protein. (B) Top 20 GSEA enrichment pathways in T24 cell lines with cisplatin treatment, 2 μg/ml for 24 h. (C) Inflam- and immune- relative enrichment pathway in T24 cell lines with cisplatin treatment, 2 μg/ml for 24 h. (D-I) Kaplan-Meier analysis of (D, F, H) overall survival rates and (E, G, I) disease-free survival rates stratified by low (n = 201) or high (n = 201) cGAS, TBK1 and IRF3 expression, respectively, from The Cancer Genome Atlas database. The median was used as the dividing line, and upregulation of cGAS, TBK1 and IRF3 expressions showed none significantly associated with overall and disease-free survival rates. DDP, cisplatin; cGAS, Cyclic GMP–AMP synthase; TBK1, TANK-binding kinase 1; IRF3, Interferon regulatory factor 3.
Figure S2. Expression of STING did not affect proliferation and cisplatin sensitivity of MB49 cell lines. (A) Different groups of tumor volumes in day 23. (B) Different groups of tumor proliferation curves. (C) Relative tumor weights of different groups. *P < 0.05, **P < 0.01. (D, E) T24 and TCCSUP cell lines were treated with 2 μg/ml cisplatin for 0 h, 4 h, 8 h, 12 h, 20 h, 28 h, respectively. CCL20 (D) and CXCL14 (E) mRNA were then analyzed by qRT-PCR. (F) Correlation analysis between cGAS-STING signaling and CCL20/CXCL14 expression in TCGA database. P < 0.001, R = 0.2.
Figure S3. Predicted immune cells infiltration percentages in TCGA bladder cancer cohorts. (A) Predicted immune cells infiltration percentages in cisplatin response bladder cancer patients (Response group, n = 50). (B) Predicted immune cells infiltration percentages in cisplatin unresponse bladder cancer patients (Unresponse group, n = 30). (C) Predicted specific immune cells infiltration difference between response group and unresponse group. (D) Basic transcription levels of cGAS in bladder cancer cell line on CCLE database. (E) Cisplatin (2 μg/ml cisplatin for 24 h) induced micronuclei in T24 and TCCSUP cell lines. Scale bar represent 5 μm.
Posted 22 Dec, 2020
Cisplatin Inhibits Bladder Cancer Proliferation Through cGAS-STING Pathway.
Posted 22 Dec, 2020
Cisplatin is a commonly used adjuvant chemotherapy for advanced bladder cancer, but its immune related mechanism is still unclear. Exploration the immune effects of cisplatin in bladder cancer would complement the comprehensive mechanism of cisplatin and provide the basis for combination therapy of cisplatin and immunotherapy in bladder cancer.
We confirmed the immune effects of cisplatin on T24 and TCCSUP bladder cancer cell lines in vitro and exploration the important function of these immune effects in bladder cancer microenvironment in mice tumor model.
We found cisplatin induced immune response in bladder cancer by RNA sequencing, and validated cGAS-STING signal was deeply involved in this response. Cisplatin induced cGAS-STING signal inhibited the proliferation of bladder cancer and increased the infiltration percentages of CD8 + T cells and dendritic cells in transplantation mice tumor model. Accumulation of dsDNA and the release of chromatin bound cGAS are important to activate downstream STING.
Our findings indicated a cisplatin related immune effects in bladder cancer, cisplatin combined with immunotherapy might have a synergistic effect for bladder cancer therapy.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6