[Nature Sub-Journal] National Taiwan University Chen Ruihua and others have discovered new targets for anti-tumor immunotherapy

[Nature Sub-Journal] National Taiwan University Chen Ruihua and others have discovered new targets for anti-tumor immunotherapy

[Nature Sub-Journal] National Taiwan University Chen Ruihua and others have discovered new targets for anti-tumor immunotherapy

Introduction: Activation of tumor-intrinsic innate immunity has been a major strategy for improving cancer immunotherapy. Previously, we reported an autophagy-promoting function of the deubiquitinating enzyme TRABID. Today, we identify a critical role for TRABID in suppressing antitumor immunity.

On May 26, researchers from National Taiwan University published the paper “TRABID inhibition activates cGAS/STING-mediated anti-tumor immunity through mitosis and autophagy dysregulation” online in “Nature Communications”, which determined the role of tumor-intrinsic TRABID in anti-tumor immunity inhibitory effect and highlight TRABID as a promising target for sensitizing solid tumors to immunotherapy .

[Nature Sub-Journal] National Taiwan University Chen Ruihua and others have discovered new targets for anti-tumor immunotherapy

https:///www.nature.com/articles/s41467-023-38784-z

Research Background

01

Immune checkpoint blockades (ICBs) targeting PD-1/PD-L1 or CTLA4 have revolutionized the current cancer treatment paradigm based on their high persistence. However, only a small fraction of cancer patients show a response. Therefore, a full understanding of ICB resistance mechanisms is needed to develop therapeutic strategies that can improve the response rate of ICBs. Accumulating evidence suggests that tumors with low lymphocytic infiltration (so-called cold tumors), high content of immunosuppressive factors, or low tumor mutational burden are often resistant to ICBs. In addition, innate cellular immunity is another factor that regulates the tumor immune microenvironment and determines tumor responses to ICBs. Therefore, drugs that trigger tumor-intrinsic innate immunity can not only induce antitumor effects but also enhance tumor responses to ICBs .

A prominent innate immune pathway is the cGAS/STING pathway, in which cGAS senses cytoplasmic double-stranded DNA to generate cGAMP. cGAMP binds and activates STING to lead to the recruitment and activation of TBK1, which in turn phosphorylates IRF3 to promote its nuclear translocation to drive the transcription of type I interferon. Furthermore, activation of IKK by STING induces the transcription of NFκB-driven inflammatory genes. Given the critical role of cGAS/STING signaling in inducing anticancer immunity, STING agonists hold promise for enhancing ICB responses to treatment of advanced cancer patients. To date, many natural and synthetic STING agonists have been tested in preclinical models, and some have entered early clinical trials. Although some promising results have been achieved, the application of STING agonists in the clinic remains challenging due to the potential pro-tumor function of the STING pathway and the persistent STING activation due to the presence of negative feedback regulation mediated by protein degradation Difficulties. Therefore, alternative therapeutic strategies may need to be developed to overcome potential limitations of STING agonists .

Research progress

02

In this study, we identified the role of tumor-intrinsic TRABID in regulating the TME by showing that TLABID deficiency induces micronuclei to activate the cGAS/STING pathway, thereby shaping an antitumor immune microenvironment. The clinical relevance of our findings was then further strengthened by identifying an inverse correlation of TRABID expression with interferon signatures and the infiltration of many antitumor immune cells in most solid cancer types. Consistent with these findings, targeting TRABID by pharmacologic inhibitors sensitizes tumors to anti-PD-1 therapy. Thus, our study describes TRABID as a potential target to improve the efficacy of anticancer immunotherapy.

[Nature Sub-Journal] National Taiwan University Chen Ruihua and others have discovered new targets for anti-tumor immunotherapy

Schematic illustration of the role of TRABID targeting in activating the cGAS/STING pathway to trigger antitumor immunity and ICB sensitization

Interestingly, the inhibitory effect of TRABID on cGAS/STING pathway activation was mediated by combined defects in mitosis and autophagy. TRABID deficiency impairs mitosis by enhancing ubiquitination and proteasomal degradation of Aurora B and Survivin, leading to further downregulation of other CPC subunits. One consequence of this mitotic defect is the formation of CIN-mediated cytoplasmic micronuclei. However, these micronuclei can be cleared by a selective autophagic process called micronucleus autophagy, in which cGAS acts as an autophagy receptor, linking micronuclei to LC3-containing autophagosomes. This process leads to autophagic degradation of micronuclei and cGAS, thereby serving as checkpoints for innate immunity. However, TRABID deficiency impairs autophagy by destabilizing the entire VPS34 complex, which would prevent micronucleus autophagy to alleviate this innate immune checkpoint.

Consistent with this notion, our study supports that autophagy defects caused by TRABID ablation partially contribute to micronucleus induction and prevent autophagic degradation of cGAS. Thus, the dual role of TRABID in mitosis and autophagy may make it a more potent target for activation of the cGAS/STING axis than for controlling chromosomal stability alone . Notably, even though the effects of TLABID deficiency on the induction of micronuclei and interferon responses were restored by the combined expression of the TLABID substrates Aurora B, Survivin and VPS34, we do not rule out that other substrates of TLABID may also be involved in the innate nuclei induced by TLABID deficiency. Likelihood of an immune response.

Taken together, our studies identify a critical role for TRABID in mitotic cell division. This effect, combined with its autophagy-promoting function, makes TRABID a potent inhibitor of cGAS/STING signaling. Targeting TRABID is a promising strategy to activate cGAS/STING-dependent antitumor immunity, thereby suppressing tumor growth and improving anticancer immunotherapy .

https:///www.nature.com/articles/s41467-023-38784-z

Note: This article aims to introduce the progress of medical research and cannot be used as a reference for treatment options. If you need health guidance, please go to a regular hospital for treatment.

[Nature Sub-Journal] National Taiwan University Chen Ruihua and others have discovered new targets for anti-tumor immunotherapy

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