cGAS/STING axis mediates a topoisomerase II inhibitor–induced tumor immunogenicity
Zining Wang, Jiemin Chen, Jie Hu, Hongxia Zhang, Feifei Xu, Wenzhuo He, Xiaojuan Wang, Mengyun Li, Wenhua Lu, Gucheng Zeng, Penghui Zhou, Peng Huang, Siyu Chen, Wende Li, Liang-ping Xia, Xiaojun Xia
Zining Wang, Jiemin Chen, Jie Hu, Hongxia Zhang, Feifei Xu, Wenzhuo He, Xiaojuan Wang, Mengyun Li, Wenhua Lu, Gucheng Zeng, Penghui Zhou, Peng Huang, Siyu Chen, Wende Li, Liang-ping Xia, Xiaojun Xia
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Research Article Immunology Oncology

cGAS/STING axis mediates a topoisomerase II inhibitor–induced tumor immunogenicity

Abstract

Checkpoint blockade antibodies have been approved as immunotherapy for multiple types of cancer, but the response rate and efficacy are still limited. There are few immunogenic cell death–inducing (ICD-inducing) drugs available that can kill cancer cells, enhance tumor immunogenicity, increase in vivo immune infiltration, and thereby boost a tumor response to immunotherapy. So far, the ICD markers have been identified as the few immunostimulating characteristics of dead cells, but whether the presence of such ICD markers on tumor cells translates into enhanced antitumor immunity in vivo is still being investigated. To identify anticancer drugs that could induce tumor cell death and boost T cell response, we performed drug screenings based on both an ICD reporter assay and a T cell activation assay. We showed that teniposide, a DNA topoisomerase II inhibitor, could induce high-mobility group box 1 (HMGB1) release and type I IFN signaling in tumor cells and that teniposide-treated tumor cells could activate antitumor T cell response both in vitro and in vivo. Mechanistically, teniposide induced tumor cell DNA damage and innate immune signaling, including NF-κB activation and stimulator of IFN genes–dependent (STING-dependent) type I IFN signaling, both of which contribute to the activation of dendritic cells and subsequent T cells. Furthermore, teniposide potentiated the antitumor efficacy of anti-PD1 in multiple types of mouse tumor models. Our findings showed that teniposide could trigger tumor immunogenicity and enabled a potential chemoimmunotherapeutic approach to potentiating the therapeutic efficacy of anti-PD1 immunotherapy.

Authors

Zining Wang, Jiemin Chen, Jie Hu, Hongxia Zhang, Feifei Xu, Wenzhuo He, Xiaojuan Wang, Mengyun Li, Wenhua Lu, Gucheng Zeng, Penghui Zhou, Peng Huang, Siyu Chen, Wende Li, Liang-ping Xia, Xiaojun Xia

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Figure 6

Teniposide induced immune cell infiltration and potentiated efficacy of anti-PD1 therapy in a CT26 mouse tumor model.

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Teniposide induced immune cell infiltration and potentiated efficacy of ...
(A–N) Mice with established CT26 tumors were treated with teniposide or vehicle on days 6 and 7 (10 mg/kg, i.p.). Tumors were isolated on day 10, and tumor-infiltrating immune cells were analyzed by flow cytometry. Data are representative of 1 of 2 independent experiments. Shown are tumor volume (A), tumor weight (B), intratumoral T cells (C), numbers of tumor-infiltrating CD8+ T cells (D), CD4+ T cells (E), and expression of activation marker CD69 (F and G) and effector molecules IFN-γ, GZMB, and TNF-α (H–J) in CD8+ T cells. (K–N) Surface expression levels of MHC-I, MHC-II, CD40, and CD86 on CD11c+ cells were determined by FACS. n = 4 mice per group. (O) Mice were injected with CD8 or CD4 depletion antibody on days 3, 6, and 9 after CT26 tumor inoculation, followed by teniposide treatment on days 7 and 8 (10 mg/kg, i.p.). Tumor volume is shown as mean ± SD. n = 5 per group. (P) Mice with established CT26 tumors were treated with teniposide, anti-PD1, or teniposide in combination with anti-PD1 at indicated time points. Tumor volume was shown as mean ± SD. n = 7 per group. (Q) Mice were inoculated with CT26-shSCR (scramble shRNA as control) or CT26-shSTING cells and then treated with indicated drugs. Tumor volume is shown as mean ± SD. n = 5 per group. *P < 0.05; **P < 0.01; ***P < 0.001, unpaired Student’s t test (A–N) or 2-way ANOVA with Bonferroni’s post test (O–Q).