Cell cycle inhibitors activate the hypoxia-induced DDX41/STING pathway to mediate antitumor immune response in liver cancer
Po Yee Wong, Cerise Yuen Ki Chan, Helen Do Gai Xue, Chi Ching Goh, Jacinth Wing Sum Cheu, Aki Pui Wah Tse, Misty Shuo Zhang, Yan Zhang, Carmen Chak Lui Wong
Po Yee Wong, Cerise Yuen Ki Chan, Helen Do Gai Xue, Chi Ching Goh, Jacinth Wing Sum Cheu, Aki Pui Wah Tse, Misty Shuo Zhang, Yan Zhang, Carmen Chak Lui Wong
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Research Article Hepatology Oncology

Cell cycle inhibitors activate the hypoxia-induced DDX41/STING pathway to mediate antitumor immune response in liver cancer

Abstract

Cell cycle inhibitors have a long history as cancer treatment. Here, we report that these inhibitors combated cancer partially via the stimulator of IFN genes (STING) signaling pathway. We demonstrated that paclitaxel (microtubule stabilizer), palbociclib (cyclin-dependent kinase 4/6 inhibitor), and AZD1152 and GSK1070916 (aurora kinase B inhibitors) have anticancer functions beyond arresting the cell cycle. They consistently caused cytosolic DNA accumulation and DNA damage, which inadvertently triggered the cytosolic DNA sensor DEAD-box helicase 41 (DDX41) and activated STING to secrete pro-inflammatory senescence-associated secretory phenotype factors (SASPs). Interestingly, we found that DDX41 was a transcriptional target of HIF. Hypoxia induced expression of DDX41 through HIF-1, making hypoxic hepatocellular carcinoma (HCC) cells more sensitive to the antimitotic agents in STING activation and SASP production. The SASPs triggered immune cell infiltration in tumors for cancer clearance. The treatment with cell cycle inhibitors, especially paclitaxel, extended survival by perturbing mouse HCC growth when used in combination with anti–PD-1. We observed a trend that paclitaxel suppressed Sting wild-type HCC more effectively than Sting-KO HCC, suggesting that STING might contribute to the antitumor effects of paclitaxel. Our study revealed the immune-mediated tumor-suppressing properties of cell cycle inhibitors and suggested combined treatment with immunotherapy as a potential therapeutic approach.

Authors

Po Yee Wong, Cerise Yuen Ki Chan, Helen Do Gai Xue, Chi Ching Goh, Jacinth Wing Sum Cheu, Aki Pui Wah Tse, Misty Shuo Zhang, Yan Zhang, Carmen Chak Lui Wong

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Figure 5

Cell cycle inhibitors induce immune surveillance in HCC tumors and promote survival in combination with an ICI.

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Cell cycle inhibitors induce immune surveillance in HCC tumors and promo...
(A and B) Cell cycle inhibitors were administrated to Trp53KO c-MycOE HCC tumor–bearing C57BL/6N mice 3 weeks after HDTVi. The tumors were harvested 28 days after paclitaxel treatment, 20 days after AZD1152 treatment, or 16 days after palbociclib treatment (n = 5 mice per group). (A) Images showing the size and morphology of HCC tumors in control and cell cycle inhibitor–treated mice. Scale: 1 cm. The liver weight was measured. (B) The tumors were fixed and prepared for paraffin-embedded slices (plots were analyzed with 3 sections from each mouse, in total 15 sections from 5 mice). CD4+ T cells, CD8+ T cells, and NK cells were detected using mouse CD4, CD8α, and KLrb1c/CD161c antibodies in IHC staining. The numbers of CD4+ T cells, CD8+ T cells, and NK cells were quantified per field in paraffin-embedded slices of control and cell cycle inhibitor–treated mice. Scatter dot plot: mean with SD. Student’s t test. (C) Vehicle control, cell cycle inhibitors alone, anti–PD-1 antibody alone, or combined treatment of cell cycle inhibitors with anti–PD-1 antibody were administrated to Trp53KO c-MycOE HCC tumor–bearing C57BL/6N mice after HDTVi. Paclitaxel and anti–PD-1 antibody were administrated 19 days and 21 days after HDTVi, respectively (n = 11 mice/group). AZD1152 and anti–PD-1 antibody were administrated 16 days and 30 days after HDTVi, respectively (n = 10 mice/group). Palbociclib and anti–PD-1 antibody were administrated 18 days and 21 days after HDTVi, respectively, continuously (n = 12 mice/group). (D) Survival curves of Sting wild-type (WT) and Sting-knockout (KO) HCC-bearing mice with vehicle control or paclitaxel treatment administrated 22 days after HDTVi (n = 12 mice/group). The percentage of surviving mice was determined over treatment time. Log-rank (Mantel-Cox) test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.