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Circadian pattern subtyping unveiling distinct immune landscapes in breast cancer patients for better immunotherapy

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Abstract

Background

While epidemiological studies have established a firm link between circadian disruption and tumorigenesis, the role and mechanism are not fully understood, complicating the design of therapeutic targets related to circadian rhythms (CR). Here, we aimed to explore the intertumoral heterogeneity of CR and elucidate its impact on the tumor microenvironment (TME), drug sensitivity, and immunotherapy.

Methods

Based on unsupervised clustering of 28 CR genes, two distinct CR subtypes (cluster-A and cluster-B) were identified in the TCGA cohort. We further constructed a circadian rhythm signature (CRS) based on the CR genes primarily responsible for clustering to quantify CR activity and to distinguish CR subtypes of individual patients from external datasets. CR subtypes were evaluated by TME characteristics, functional annotation, clinical features, and therapeutic response.

Results

The cluster-B (low-CRS) group was characterized by highly enriched immune-related pathways, high immune cell infiltration, and high anti-tumor immunity, while the cluster-A (high-CRS) group was associated with immunosuppression, synaptic transmission pathways, EMT activation, poor prognosis, and drug resistance. Immunohistochemistry (IHC) results demonstrated that high CD8+ T cell infiltration was associated with low-CR-protein expression. Importantly, patients with low CRS were more likely to benefit from immune checkpoint blockade (ICB) treatment, possibly due to their higher tumor mutation burden (TMB), increased immune checkpoint expression, and higher proportion of “hot” immunophenotype.

Conclusion

In a nutshell, the cross talk in CR could reflect the TME immunoreactivity in breast cancer. Besides providing the first comprehensive pathway-level analysis of CR in breast cancer, this work highlights the potential clinical utility of CR for immunotherapy.

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Availability of data and materials

All online data and tools described in this article are available from their web servers and are free for any scientist to use for non-commercial purposes. Further information and source code are available from the corresponding author upon reasonable request.

Abbreviations

BC:

Breast cancer

CR:

Circadian rhythm

CRS:

Circadian rhythm signature

ER:

Estrogen receptor

ICB:

Immune checkpoint blockade

IPS:

Immunophenoscore

TIDE:

Tumor Immune Dysfunction and Evolution

TME:

Tumor microenvironment

TMB:

Tumor mutation burden

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Acknowledgements

The authors highly appreciate Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) database for providing the transcriptome and clinical information.

Funding

This research was funded by the National Natural Science Foundation of China, grant number 81560464 and 31960152 (D.L.).

Author information

Author notes

  1. Siqi Xiong and Wenqiang Zhu have contributed equally to this paper.

Authors and Affiliations

  1. School of Medicine, Queen Mary Institute, Nanchang University, Nanchang, 330006, China

    Siqi Xiong

  2. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University, Nanchang, 330006, China

    Wenqiang Zhu, Zhuoqi Liu & Daya Luo

  3. Department of Pathology, First Hospital of Nanchang City, Nanchang, 330008, Jiangxi, China

    Liqing Wu

  4. Pathology Department, Infectious Diseases Hospital of Nanchang University, Nanchang, 330006, China

    Tianmin Zhou & Wu Wang

  5. The First Clinical Department, Nanchang University, Nanchang, 330006, China

    Ouyang Zhang

  6. Department of Pathology, School of Basic Medical Sciences, Nanchang University, Nanchang, 330006, China

    Xiaoliang Xiong

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  1. Siqi Xiong
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Contributions

SX performed the bioinformatic analysis, statistical analysis, and drafting of the manuscript. WZ performed the experiment. LW, TZ, WW, OZ, and XX contributed to the investigation, methodology, and data curation. ZL and DL conceived of the study, participated in its design, and revised it substantially. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Zhuoqi Liu or Daya Luo.

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Conflict of interest

The authors declare that there are no conflicts of interest.

Ethics approval and consent to participate

This study was approved by the institutional review board of the First Affiliated Hospital of Nanchang University, and written informed consent was obtained from all patients.

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Xiong, S., Zhu, W., Wu, L. et al. Circadian pattern subtyping unveiling distinct immune landscapes in breast cancer patients for better immunotherapy. Cancer Immunol Immunother 72, 3293–3307 (2023). https://doi.org/10.1007/s00262-023-03495-3

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