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 6

Cell cycle inhibitors trigger immune response via the DDX41/STING pathway.

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Cell cycle inhibitors trigger immune response via the DDX41/STING pathwa...
Schematic diagram showing cell cycle inhibitors trigger immune response via the DDX41/STING pathway. HCC tumor is highly hypoxic, which induces the upregulation of DDX41 expression in cells. Since both hypoxia and overexpression of DDX41 are detrimental to cells, cell cycle inhibitors are used to induce cytosolic DNA accumulation and trigger the activation of DDX41 as a cytosolic DNA sensor. The activated DDX41 binds to both the cytosolic DNA and STING. Upon activation, STING dimerizes and translocates from the ER to Golgi apparatus and recruits TBK1. TBK1 autophosphorylates and further phosphorylates STING and facilitates the recruitment and activation of IRF3 and IRF7. IRF3 and IRF7 form homodimer or heterodimer and translocate to nucleus for SASP expression. STING also activates IκB kinase (IKK), which then phosphorylates and inhibits the inhibitor of NF-κB (IκB). Without the binding of IκB, the NF-κB translocates to nucleus for SASP expression. The secreted SASPs recruit the infiltration of both innate and adaptive immune cells, especially NK cells, CD4+ T cells, and CD8+ T cells, to the HCC tumor core for cancer clearance. The cytotoxic potential of those infiltrated immune cells can be further enhanced by using ICIs, for example anti–PD-1 antibody, which suggests the potential of combined treatment of cell cycle inhibitors with immunotherapy.