Targeting Both Death and Paracaspase Domains of MALT1 with Antisense Oligonucleotides Overcomes Resistance to Immune-checkpoint Inhibitors

Overview

Journal Nat Cancer

Specialty Oncology

Date 2025 Mar 13

PMID 40075237

Authors

Yuwei Tao

Chen Tian

Shaolong Qi

Ziqi Jia

Zheng Xu

Jingjing Meng

Guoyuan Xu

Haitian Hu

Xuxiang Wang

Tengjiang Zhang

Huiwen You

Xun Lan

Xin Lin

Guocan Yu

Haitao Zhou

Jiaqi Liu

Hanqiu Zheng

Affiliations

Soon will be listed here.

Abstract

Targeting MALT1's paracaspase activity has been explored for B cell lymphoma and solid tumors. While the role of MALT1 in promoting cancer cell proliferation has been investigated, its involvement in immune evasion is unclear. Here we report that MALT1 promotes immune evasion through its paracaspase and death domain. In a paracaspase-dependent manner, MALT1 protects CD274 mRNA from degradation by its cleavage of ROQUIN1 and ROQUIN2. In a death-domain-dependent manner, MALT1 promotes the proliferation and polarization of tumor-associated macrophages to generate an immunosuppressive tumor microenvironment. Targeting MALT1 with antisense oligonucleotides inhibits PD-L1 expression in patient-derived tumor cells and suppresses the proliferation and M2-like polarization of tumor-associated macrophages isolated from patients with cancer. In preclinical models of solid tumors in female mice, treatment with MALT1 antisense oligonucleotides overcomes resistance to immune-checkpoint inhibitors. Together, our study demonstrates that targeting MALT1 is a potential strategy to overcome immune-checkpoint inhibitor resistance.

References

Kalbasi A, Ribas A . Tumour-intrinsic resistance to immune checkpoint blockade. Nat Rev Immunol. 2019; 20(1):25-39. PMC: 8499690. DOI: 10.1038/s41577-019-0218-4. View

Pan D, Kobayashi A, Jiang P, Ferrari de Andrade L, Tay R, Luoma A . A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing. Science. 2018; 359(6377):770-775. PMC: 5953516. DOI: 10.1126/science.aao1710. View

Ishizuka J, Manguso R, Cheruiyot C, Bi K, Panda A, Iracheta-Vellve A . Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade. Nature. 2018; 565(7737):43-48. PMC: 7241251. DOI: 10.1038/s41586-018-0768-9. View

Cassetta L, Pollard J . A timeline of tumour-associated macrophage biology. Nat Rev Cancer. 2023; 23(4):238-257. DOI: 10.1038/s41568-022-00547-1. View

Yu J, Green M, Li S, Sun Y, Journey S, Choi J . Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination. Nat Med. 2021; 27(1):152-164. PMC: 8095049. DOI: 10.1038/s41591-020-1131-x. View

Obradovic A, Chowdhury N, Haake S, Ager C, Wang V, Vlahos L . Single-cell protein activity analysis identifies recurrence-associated renal tumor macrophages. Cell. 2021; 184(11):2988-3005.e16. PMC: 8479759. DOI: 10.1016/j.cell.2021.04.038. View

Argyle D, Kitamura T . Targeting Macrophage-Recruiting Chemokines as a Novel Therapeutic Strategy to Prevent the Progression of Solid Tumors. Front Immunol. 2018; 9:2629. PMC: 6243037. DOI: 10.3389/fimmu.2018.02629. View

Ruland J, Duncan G, Wakeham A, Mak T . Differential requirement for Malt1 in T and B cell antigen receptor signaling. Immunity. 2003; 19(5):749-58. DOI: 10.1016/s1074-7613(03)00293-0. View

Rebeaud F, Hailfinger S, Posevitz-Fejfar A, Tapernoux M, Moser R, Rueda D . The proteolytic activity of the paracaspase MALT1 is key in T cell activation. Nat Immunol. 2008; 9(3):272-81. DOI: 10.1038/ni1568. View

10.

Gehring T, Erdmann T, Rahm M, Grass C, Flatley A, ONeill T . MALT1 Phosphorylation Controls Activation of T Lymphocytes and Survival of ABC-DLBCL Tumor Cells. Cell Rep. 2019; 29(4):873-888.e10. DOI: 10.1016/j.celrep.2019.09.040. View

11.

Blonska M, Lin X . NF-κB signaling pathways regulated by CARMA family of scaffold proteins. Cell Res. 2010; 21(1):55-70. PMC: 3193407. DOI: 10.1038/cr.2010.182. View

12.

Sun L, Deng L, Ea C, Xia Z, Chen Z . The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. Mol Cell. 2004; 14(3):289-301. DOI: 10.1016/s1097-2765(04)00236-9. View

13.

Coornaert B, Baens M, Heyninck K, Bekaert T, Haegman M, Staal J . T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-kappaB inhibitor A20. Nat Immunol. 2008; 9(3):263-71. DOI: 10.1038/ni1561. View

14.

Hailfinger S, Nogai H, Pelzer C, Jaworski M, Cabalzar K, Charton J . Malt1-dependent RelB cleavage promotes canonical NF-kappaB activation in lymphocytes and lymphoma cell lines. Proc Natl Acad Sci U S A. 2011; 108(35):14596-601. PMC: 3167514. DOI: 10.1073/pnas.1105020108. View

15.

Staal J, Driege Y, Bekaert T, Demeyer A, Muyllaert D, Van Damme P . T-cell receptor-induced JNK activation requires proteolytic inactivation of CYLD by MALT1. EMBO J. 2011; 30(9):1742-52. PMC: 3101995. DOI: 10.1038/emboj.2011.85. View

16.

Jeltsch K, Hu D, Brenner S, Zoller J, Heinz G, Nagel D . Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote T(H)17 differentiation. Nat Immunol. 2014; 15(11):1079-89. DOI: 10.1038/ni.3008. View

17.

Uehata T, Iwasaki H, Vandenbon A, Matsushita K, Hernandez-Cuellar E, Kuniyoshi K . Malt1-induced cleavage of regnase-1 in CD4(+) helper T cells regulates immune activation. Cell. 2013; 153(5):1036-49. DOI: 10.1016/j.cell.2013.04.034. View

18.

Xia X, Zhou W, Guo C, Fu Z, Zhu L, Li P . Glutaminolysis Mediated by MALT1 Protease Activity Facilitates PD-L1 Expression on ABC-DLBCL Cells and Contributes to Their Immune Evasion. Front Oncol. 2019; 8:632. PMC: 6305595. DOI: 10.3389/fonc.2018.00632. View

19.

Di Pilato M, Kim E, Cadilha B, Prussmann J, Nasrallah M, Seruggia D . Targeting the CBM complex causes T cells to prime tumours for immune checkpoint therapy. Nature. 2019; 570(7759):112-116. PMC: 6656391. DOI: 10.1038/s41586-019-1215-2. View

20.

Cheng L, Deng N, Yang N, Zhao X, Lin X . Malt1 Protease Is Critical in Maintaining Function of Regulatory T Cells and May Be a Therapeutic Target for Antitumor Immunity. J Immunol. 2019; 202(10):3008-3019. DOI: 10.4049/jimmunol.1801614. View