RGS2 is an innate immune checkpoint for suppressing Gαq mediated IFNγ generation and lung injury
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ABSTRACT:
PROVIDER: PRJNA1156693 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30545186_1.fastq.gz | Fastqsanger.gz | |||
| SRR30545186_2.fastq.gz | Fastqsanger.gz | |||
| SRR30545187_1.fastq.gz | Fastqsanger.gz | |||
| SRR30545187_2.fastq.gz | Fastqsanger.gz | |||
| SRR30545188_1.fastq.gz | Fastqsanger.gz |
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Project description:Infections can trigger the release of IFNγ, a type II interferon, which exacerbates tissue inflammation and may lead to severe acute lung injury (ALI). However, the regulatory mechanisms of IFNγ production in the lungs are not fully understood. In this study, we identified RGS2 as a crucial regulator of IFNγ levels in the lungs during infection. The absence of RGS2 led to persistently elevated IFNγ production in macrophages, resulting in unresolved inflammatory lung damage. Notably, this effect was absent in RGS2-deficient chimeric mice that received wild-type bone marrow or RGS2 expression in alveolar macrophages (AMs), as well as in those treated with an IFNγ-blocking antibody. RGS2 exerts its regulatory role by inhibiting Gαq-mediated IFNγ production and inflammatory signaling in AMs. Consequently, the inhibition of Gαq in RGS2-deficient mice prevented IFNγ production in AMs and shifted their transcriptomic profile from an inflammatory to a reparative state. These findings suggest that the RGS2-Gαq signaling pathway could be a promising therapeutic target for mitigating inflammatory lung injury.
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Project description:While immune checkpoint blockade therapy (ICBT) benefits cancer patients, many fail to maintain their response due to adaptive resistance mechanisms. IFNγ is critical for cellular immunity, but also promotes adaptive resistance to ICBT. We have established a role for PARP14 in mediating IFNγ-induced adaptive resistance. We confirm that chronic pre-treatment of tumour cells with IFNγ confers resistance to α-PD-1 antibodies in syngeneic mouse tumour models. We identified that PARP14 was consistently upregulated in cancer cells treated chronically with IFNγ as well as in IFNγ-high melanoma samples. Further, we showed that PARP14 knockdown or pharmacological inhibition restores sensitivity to α-PD-1 antibodies accompanied by increased immune cell infiltration into tumours but the decreased presence of regulatory T cells. RNA sequencing analysis of tumours and cultured cells treated with PARP14 inhibitor showed an upregulation of inflammatory-related pathways. In conclusion, PARP14 is an actionable target for reversing IFNγ-driven adaptive resistance to ICBT.
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Project description:While immune checkpoint blockade therapy (ICBT) benefits cancer patients, many fail to maintain their response due to adaptive resistance mechanisms. IFNγ is critical for cellular immunity, but also promotes adaptive resistance to ICBT. We have established a role for PARP14 in mediating IFNγ-induced adaptive resistance. We confirm that chronic pre-treatment of tumour cells with IFNγ confers resistance to α-PD-1 antibodies in syngeneic mouse tumour models. We identified that PARP14 was consistently upregulated in cancer cells treated chronically with IFNγ as well as in IFNγ-high melanoma samples. Further, we showed that PARP14 knockdown or pharmacological inhibition restores sensitivity to α-PD-1 antibodies accompanied by increased immune cell infiltration into tumours but the decreased presence of regulatory T cells. RNA sequencing analysis of tumours and cultured cells treated with PARP14 inhibitor showed an upregulation of inflammatory-related pathways. In conclusion, PARP14 is an actionable target for reversing IFNγ-driven adaptive resistance to ICBT.
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Project description:While immune checkpoint blockade therapy (ICBT) benefits cancer patients, many fail to maintain their response due to adaptive resistance mechanisms. IFNγ is critical for cellular immunity, but also promotes adaptive resistance to ICBT. We have established a role for PARP14 in mediating IFNγ-induced adaptive resistance. We confirm that chronic pre-treatment of tumour cells with IFNγ confers resistance to α-PD-1 antibodies in syngeneic mouse tumour models. We identified that PARP14 was consistently upregulated in cancer cells treated chronically with IFNγ as well as in IFNγ-high melanoma samples. Further, we showed that PARP14 knockdown or pharmacological inhibition restores sensitivity to α-PD-1 antibodies accompanied by increased immune cell infiltration into tumours but the decreased presence of regulatory T cells. RNA sequencing analysis of tumours and cultured cells treated with PARP14 inhibitor showed an upregulation of inflammatory-related pathways. In conclusion, PARP14 is an actionable target for reversing IFNγ-driven adaptive resistance to ICBT.
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