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

Jul 18, 2023Cancer immunology, immunotherapy : CII

Daily immune system patterns reveal different types of breast cancer for improved immunotherapy

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Two distinct circadian rhythm subtypes were identified in breast cancer, with cluster-B showing low circadian rhythm activity and enriched immune-related pathways.

Cluster-B (low circadian rhythm activity) is associated with high immune cell infiltration and anti-tumor immunity.
Cluster-A (high circadian rhythm activity) is linked to immunosuppression and poor prognosis.
High CD8T cell infiltration correlates with low circadian rhythm protein expression.
Patients with low circadian rhythm activity may benefit more from immune checkpoint blockade treatment.
The study suggests a relationship between circadian rhythm activity and the tumor microenvironment in breast cancer.

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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 CD8T 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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Circadian pattern subtyping unveiling distinct immune landscapes in breast cancer patients for better immunotherapy

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