Targeting of GSDMD Sensitizes HCC to Anti-PD-1 by Activating CGAS Pathway and Downregulating PD-L1 Expression

Overview

Journal J Immunother Cancer

Specialties Allergy & Immunology
Oncology
Pharmacology

Date 2022 Jun 10

PMID 35688553

Authors

Tingting Lv

Xiaofeng Xiong

Wei Yan

Mei Liu

Hongwei Xu

Qin He

Affiliations

Soon will be listed here.

Abstract

Background: Gasdermin D (GSDMD) is well known as a downstream of inflammasomes. However, the roles of GSDMD itself in hepatocellular carcinoma (HCC) remain unclear.

Methods: Two independent cohorts of patients with HCC were analyzed to evaluate the pathological relevance of GSDMD/pTBK1/PD-L1. GSDMD knockout (GSDMD-/-) mice, Alb-Cre mice administered with an adeno-associated virus (AAV) vector that expressed the gasdermin-N domain (AAV9-FLEX-GSDMD-N) and their wild-type littermates were used to induce hepatocarcinogenesis or metastatic HCC. Combination of anti-programmed cell death protein-1 (PD-1) and GSDMD inhibitor dimethyl fumarate (DMF) was used to test for improved therapeutic efficacy. RNA sequencing was used to explore the mechanisms how GSDMD promoted HCC progression.

Results: The expression of GSDMD and GSDMD-N was upregulated in HCC tissues or metastatic HCC tissues and positive GSDMD expression indicated grim prognosis. Diethylnitrosamine/carbon tetrachloride or thioacetamide-treated GSDMD-/- mice exhibited decreased liver tumors. In contrast, AAV9-FLEX-GSDMD-N promoted hepatocarcinogenesis. RNA sequencing manifested that knockout of GSDMD impacted the cyclic GMP-AMP synthase (cGAS) pathway and immune-associated pathway. GSDMD damped cGAS activation by promoting autophagy via outputting potassium (K+) and promoted programmed death ligand-1 (PD-L1) expression by histone deacetylases/signal transducer and activator of transcription 1 (STAT1)-induced transactivation of PD-L1 via importing calcium (Ca2+). High Mobility Group Box 1/toll-like receptor 4 (TLR4)/caspase-1 pathway contributed to the overexpression and cleavage of GSDMD. Anti-PD-1 combining with DMF largely impaired HCC progression and metastasis.

Conclusions: Targeting GSDMD could promote expression of interferons through inactivation of cGAS pathway and downregulated the PD-L1 expression. Therefore, combined anti-PD-1 and GSDMD inhibitor might serve as an effective treatment option for patients with HCC with GSDMD upregulation.

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References

Conos S, Chen K, De Nardo D, Hara H, Whitehead L, Nunez G . Active MLKL triggers the NLRP3 inflammasome in a cell-intrinsic manner. Proc Natl Acad Sci U S A. 2017; 114(6):E961-E969. PMC: 5307433. DOI: 10.1073/pnas.1613305114. View

Ma C, Yang D, Wang B, Wu C, Wu Y, Li S . Gasdermin D in macrophages restrains colitis by controlling cGAS-mediated inflammation. Sci Adv. 2020; 6(21):eaaz6717. PMC: 7314554. DOI: 10.1126/sciadv.aaz6717. View

Prindle A, Liu J, Asally M, Ly S, Garcia-Ojalvo J, Suel G . Ion channels enable electrical communication in bacterial communities. Nature. 2015; 527(7576):59-63. PMC: 4890463. DOI: 10.1038/nature15709. View

Gong Y, Guy C, Olauson H, Becker J, Yang M, Fitzgerald P . ESCRT-III Acts Downstream of MLKL to Regulate Necroptotic Cell Death and Its Consequences. Cell. 2017; 169(2):286-300.e16. PMC: 5443414. DOI: 10.1016/j.cell.2017.03.020. View

Zhu M, Cao L, Xiong S, Sun H, Wu Z, Bian J . Na/K-ATPase-dependent autophagy protects brain against ischemic injury. Signal Transduct Target Ther. 2020; 5(1):55. PMC: 7237650. DOI: 10.1038/s41392-020-0153-7. View

Vodnala S, Eil R, Kishton R, Sukumar M, Yamamoto T, Ha N . T cell stemness and dysfunction in tumors are triggered by a common mechanism. Science. 2019; 363(6434). PMC: 8194369. DOI: 10.1126/science.aau0135. View

Yan W, Chang Y, Liang X, Cardinal J, Huang H, Thorne S . High-mobility group box 1 activates caspase-1 and promotes hepatocellular carcinoma invasiveness and metastases. Hepatology. 2012; 55(6):1863-75. PMC: 4610360. DOI: 10.1002/hep.25572. View

Zhang X, Bai X, Chen Z . Structures and Mechanisms in the cGAS-STING Innate Immunity Pathway. Immunity. 2020; 53(1):43-53. DOI: 10.1016/j.immuni.2020.05.013. View

Liu Y, Yan W, Tohme S, Chen M, Fu Y, Tian D . Hypoxia induced HMGB1 and mitochondrial DNA interactions mediate tumor growth in hepatocellular carcinoma through Toll-like receptor 9. J Hepatol. 2015; 63(1):114-21. PMC: 4475488. DOI: 10.1016/j.jhep.2015.02.009. View

10.

He W, Wan H, Hu L, Chen P, Wang X, Huang Z . Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion. Cell Res. 2015; 25(12):1285-98. PMC: 4670995. DOI: 10.1038/cr.2015.139. View

11.

Cui Y, Yu H, Zheng X, Peng R, Wang Q, Zhou Y . SENP7 Potentiates cGAS Activation by Relieving SUMO-Mediated Inhibition of Cytosolic DNA Sensing. PLoS Pathog. 2017; 13(1):e1006156. PMC: 5271409. DOI: 10.1371/journal.ppat.1006156. View

12.

Llovet J, Kelley R, Villanueva A, Singal A, Pikarsky E, Roayaie S . Hepatocellular carcinoma. Nat Rev Dis Primers. 2021; 7(1):6. DOI: 10.1038/s41572-020-00240-3. View

13.

Soufi A, Garcia M, Jaroszewicz A, Osman N, Pellegrini M, Zaret K . Pioneer transcription factors target partial DNA motifs on nucleosomes to initiate reprogramming. Cell. 2015; 161(3):555-568. PMC: 4409934. DOI: 10.1016/j.cell.2015.03.017. View

14.

Miao E, Leaf I, Treuting P, Mao D, Dors M, Sarkar A . Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria. Nat Immunol. 2010; 11(12):1136-42. PMC: 3058225. DOI: 10.1038/ni.1960. View

15.

Mukherjee A, Roy S, Patidar A, Bodhale N, Dandapat J, Saha B . TLR2 dimer-specific ligands selectively activate protein kinase C isoforms in Leishmania infection. Immunology. 2021; 164(2):318-331. PMC: 8442242. DOI: 10.1111/imm.13373. View

16.

Li M, Lu Y, Li Y, Tong L, Gu X, Meng J . Transketolase Deficiency Protects the Liver from DNA Damage by Increasing Levels of Ribose 5-Phosphate and Nucleotides. Cancer Res. 2019; 79(14):3689-3701. DOI: 10.1158/0008-5472.CAN-18-3776. View

17.

Humphries F, Shmuel-Galia L, Ketelut-Carneiro N, Li S, Wang B, Nemmara V . Succination inactivates gasdermin D and blocks pyroptosis. Science. 2020; 369(6511):1633-1637. PMC: 8744141. DOI: 10.1126/science.abb9818. View

18.

Andersson U, Tracey K . HMGB1 is a therapeutic target for sterile inflammation and infection. Annu Rev Immunol. 2011; 29:139-62. PMC: 4536551. DOI: 10.1146/annurev-immunol-030409-101323. View

19.

Sun C, Mezzadra R, Schumacher T . Regulation and Function of the PD-L1 Checkpoint. Immunity. 2018; 48(3):434-452. PMC: 7116507. DOI: 10.1016/j.immuni.2018.03.014. View

20.

Russo H, Rathkey J, Boyd-Tressler A, Katsnelson M, Abbott D, Dubyak G . Active Caspase-1 Induces Plasma Membrane Pores That Precede Pyroptotic Lysis and Are Blocked by Lanthanides. J Immunol. 2016; 197(4):1353-67. PMC: 4976007. DOI: 10.4049/jimmunol.1600699. View