Unraveling the role of M1 macrophage and CXCL9 in predicting immune checkpoint inhibitor efficacy through multicohort analysis and single‐cell RNA sequencing

Yu, Yunfang; Chen, Haizhu; Ouyang, Wenhao; Zeng, Jin; Huang, Hong; Mao, Luhui; Jia, Xueyuan; Guan, Taihua; Wang, Zehua; Lin, Ruichong; Huang, Zhenjun; Yin, Hanqi; Yao, Herui; Zhang, Kang

doi:10.1002/mco2.471

Cited by 5 publications

(1 citation statement)

References 44 publications

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“…The APOBEC3 family is highly expressed in macrophages, lymphoid cells, and dendritic cells, and dysregulated APOBEC3 activity has been implicated in genome mutagenesis in cancer 90,91 . APOBEC3G was notably upregulated in MSG tissues obtained from SS lymphoma patients 92 , which exhibited a more widespread distribution across myeloid, B-lymphocyte, and T-lymphocyte clusters 93 . Furthermore, our research colocalized the genetic in uences on APOBEC3G expression with those of in ammatory cytokines.…”

Section: Discussionmentioning

confidence: 99%

Interplay of Interferon signalling gene expression, DNA Methylation, and inflammatory cytokines in Sjögren’s Syndrome: a multi-omics Mendelian randomization study

He,

Pang,

Shan

et al. 2024

Preprint

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Background Abnormal activation of the interferon (IFN) signalling plays a central role in the progression of Sjögren’s syndrome (SS). However, the causal relationship between IFN signalling and SS remains unclear, with complex interactions existing among genetic variants, epigenetic modifications, inflammatory cytokine levels, and the expression of IFN-associated genes. Thus, in order to reveal the potential causality and interaction mechanisms among IFN-associated gene expression, DNA methylation, inflammatory cytokines, and SS, our analysis was conducted using a multi-omics summary data-based Mendelian randomization (SMR) approach. Methods Genes associated with IFN signalling were extracted from the GeneCards database, and transcriptomic datasets for SS were obtained from the Gene Expression Omnibus (GEO) database. Linear regression models and meta-analysis identified IFN-associated differentially expressed genes (DEGs) in SS. Using a three-step SMR method, an integrated analysis of expression quantitative trait loci (eQTLs) and DNA methylation QTLs (mQTLs) with SS genome-wide association study (GWAS) from FinnGen was performed to reveal causal relationships between blood IFN-associated gene expression, DNA methylation, and SS pathogenesis. Then use SS GWAS data from UK Biobank for validation. Through colocalization analysis, integrating analysis of blood IFN-associated causal genes eQTLs with inflammatory cytokines GWAS was performed to identify potential interactions between blood IFN gene expression and inflammatory cytokines. Meanwhile, minor salivary gland (MSG) tissue eQTLs from GTEx V8 and SS GWAS were integrated by SMR to identify MSG IFN-associated causal genes. Through colocalization analysis, integrating analysis of MSG IFN-associated causal genes eQTLs with inflammatory cytokines GWAS was performed to identify potential interactions between IFN-associated causal gene expression in MSG and inflammatory cytokines. Results A total of 331 IFN-associated DEGs were identified by integrative analysis of three transcriptomic datasets and 711 IFN-associated genes. These DEGs are predominantly enriched in T-cells, macrophages, monocytes, and natural killer cells. Five blood IFN-associated genes: SH2B3, LGALS9, CD40, GRB2, and DTX3L, were identified as SS-causal genes using a three-step SMR approach. Three of these genes, LGALS9, SH2B3, and CD40, are involved in the interaction between gene expression and inflammatory cytokines through colocalization analysis. Furthermore, SMR and colocalization analysis also identified thirteen putative MSG IFN-associated genes, four of which were involved in gene–inflammatory cytokines interactions: APOBEC3G, IFI27L2, TMEM50B, and SH2B3. Conclusions This study uncovered a causal relationship between interferon signalling and SS, revealing complex interactions among IFN-associated causal gene expression, DNA methylation, and inflammatory cytokines in SS pathogenesis. This offers new evidence for the involvement of interferon signalling in the pathogenic process of SS and provides fresh insights into the interactions among epigenetic, genetic variants, and inflammatory cytokines for in-depth studies of pathogenesis and molecular mechanisms.

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Section: Discussionmentioning

confidence: 99%

Interplay of Interferon signalling gene expression, DNA Methylation, and inflammatory cytokines in Sjögren’s Syndrome: a multi-omics Mendelian randomization study

He,

Pang,

Shan

et al. 2024

Preprint

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Combined pyrotinib and fulvestrant for hormone receptor‐positive and HER2‐positive metastatic breast cancer: A multicenter, single‐arm, phase II trial

Zhao,

Yu,

Ren

et al. 2024

MedComm

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This multicenter, single‐arm, phase II clinical trial (NCT04034589) evaluated the efficacy and safety of pyrotinib combined with fulvestrant in patients with HR‐positive/HER2‐positive metastatic breast cancer who had experienced trastuzumab treatment failure. A total of 46 patients were enrolled, receiving pyrotinib orally once daily and fulvestrant intramuscularly on days 1 and 15 of cycle 1, followed by monthly doses on day 1. The primary endpoint was progression‐free survival (PFS), while secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. The median PFS was 18.2 months (95% CI, 11.9–31.1) overall, 19.5 months (95% CI, 10.6–NA) for those receiving the combination as first‐line therapy, and 18.4 months (95% CI, 16.7–NA) for patients with brain metastases. Median OS was not reached, with a 3‐year OS rate of 75.2% (95% CI, 62.8–90.2%). The ORR was 32.5%, and the DCR was 97.5%. Responses were observed in patients with low tumor mutation burden and ZNF217 mutation. Importantly, no grade 4 or higher treatment‐related adverse events or deaths were reported, indicating a favorable safety profile. In conclusion, the combination of pyrotinib and fulvestrant demonstrated promising antitumor activity and acceptable safety in HR‐positive/HER2‐positive metastatic breast cancer patients.

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Myeloid effector cells in cancer

Schol,

van Elsas,

Middelburg

et al. 2024

Cancer Cell

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Unraveling the role of M1 macrophage and CXCL9 in predicting immune checkpoint inhibitor efficacy through multicohort analysis and single‐cell RNA sequencing

Cited by 5 publications

References 44 publications

Interplay of Interferon signalling gene expression, DNA Methylation, and inflammatory cytokines in Sjögren’s Syndrome: a multi-omics Mendelian randomization study

Interplay of Interferon signalling gene expression, DNA Methylation, and inflammatory cytokines in Sjögren’s Syndrome: a multi-omics Mendelian randomization study

Combined pyrotinib and fulvestrant for hormone receptor‐positive and HER2‐positive metastatic breast cancer: A multicenter, single‐arm, phase II trial

Myeloid effector cells in cancer

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