Tailoring therapies to counter the divergent immune landscapes of breast cancer

Attalla, Sherif Samer; Taifour, Tarek; Muller, William J.

doi:10.3389/fcell.2023.1111796

Cited by 3 publications

(2 citation statements)

References 203 publications

(247 reference statements)

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“…Foxp3 + regulatory T lymphocytes (Treg) are identified as the dominant mechanism of immune escape from tumor‐specific effector T lymphocyte responses 4 . They are regarded as a major obstacle to effective cancer immunotherapy, hence targeting Treg could be a promising approach for BC immunotherapy, such as immune checkpoint inhibitors (ICI) 5 . Treg infiltrating reflects real‐time anti‐tumor immune response and helps oncologists to assess patients' prognosis 6 .…”

Section: Introductionmentioning

confidence: 99%

“… 4 They are regarded as a major obstacle to effective cancer immunotherapy, hence targeting Treg could be a promising approach for BC immunotherapy, such as immune checkpoint inhibitors (ICI). 5 Treg infiltrating reflects real‐time anti‐tumor immune response and helps oncologists to assess patients' prognosis. 6 Yet, biopsies and pathologic reviews are incapable to reflect tumor heterogeneity, due to sampling bias.…”

Section: Introductionmentioning

confidence: 99%

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Profiling regulatory T lymphocytes within the tumor microenvironment of breast cancer via radiomics

Jiang,

Wu,

Yang

et al. 2023

Cancer Medicine

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ObjectiveTo generate an image‐driven biomarker (Rad_score) to predict tumor‐infiltrating regulatory T lymphocytes (Treg) in breast cancer (BC).MethodsOverall, 928 BC patients were enrolled from the Cancer Genome Atlas (TCGA) for survival analysis; MRI (n = 71 and n = 30 in the training and validation sets, respectively) from the Cancer Imaging Archive (TCIA) were retrieved and subjected to repeat least absolute shrinkage and selection operator for feature reduction. The radiomic scores (rad_score) for Treg infiltration estimation were calculated via support vector machine (SVM) and logistic regression (LR) algorithms, and validated on the remaining patients.ResultsLandmark analysis indicated Treg infiltration was a risk factor for BC patients in the first 5 years and after 10 years of diagnosis (p = 0.007 and 0.018, respectively). Altogether, 108 radiomic features were extracted from MRI images, 4 of which remained for model construction. Areas under curves (AUCs) of the SVM model were 0.744 (95% CI 0.622–0.867) and 0.733 (95% CI 0.535–0.931) for training and validation sets, respectively, while for the LR model, AUCs were 0.771 (95% CI 0.657–0.885) and 0.724 (95% CI 0.522–0.926). The calibration curves indicated good agreement between prediction and true value (p > 0.05), and DCA shows the high clinical utility of the radiomic model. Rad_score was significantly correlated with immune inhibitory genes like CTLA4 and PDCD1.ConclusionsHigh Treg infiltration is a risk factor for patients with BC. The Rad_score formulated on radiomic features is a novel tool to predict Treg abundance in the tumor microenvironment.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Profiling regulatory T lymphocytes within the tumor microenvironment of breast cancer via radiomics

Jiang,

Wu,

Yang

et al. 2023

Cancer Medicine

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The tumor-derived cytokine Chi3l1 induces neutrophil extracellular traps that promote T cell exclusion in triple-negative breast cancer

Taifour,

Attalla,

Zuo

et al. 2023

Immunity

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HER2Δ16 Engages ENPP1 to Promote an Immune-Cold Microenvironment in Breast Cancer

Attalla,

Boucher,

Proud

et al. 2023

Cancer Immunology Research

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The tumor immune microenvironment (TIME) is a critical determinant of therapeutic response. However, the mechanisms regulating its modulation are not fully understood. HER216, an oncogenic splice variant of the human epidermal growth factor receptor (HER2), has been implicated in breast cancer and other tumor types as a driver of tumorigenesis and metastasis. Nevertheless, the underlying mechanisms of HER2Δ16-mediated oncogenicity remain poorly understood. Here, we show that HER2∆16 expression is not exclusive to the clinically HER2+ subtype and associates with a poor clinical outcome in breast cancer. To understand how HER2 variants modulated the tumor microenvironment, we generated transgenic mouse models expressing either proto-oncogenic HER2 or HER2∆16 in the mammary epithelium. We found that HER2∆16 tumors were immune cold, characterized by low immune infiltrate and an altered cytokine profile. Using an epithelial cell surface proteomic approach, we identified ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) as a functional regulator of the immune cold microenvironment. We generated a knock-in model of HER2Δ16 under the endogenous promoter to understand the role of Enpp1 in aggressive HER2+ breast cancer. Knockdown of Enpp1 in HER2Δ16-derived tumor cells resulted in decreased tumor growth, which correlated with increased T-cell infiltration. These findings suggest that HER2Δ16-dependent Enpp1 activation associates with aggressive HER2+ breast cancer through its immune modulatory function. Our study provides a better understanding of the mechanisms underlying HER2Δ16-mediated oncogenicity and highlights ENPP1 as a potential therapeutic target in aggressive HER2+ breast cancer.

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Tailoring therapies to counter the divergent immune landscapes of breast cancer

Cited by 3 publications

References 203 publications

Profiling regulatory T lymphocytes within the tumor microenvironment of breast cancer via radiomics

Profiling regulatory T lymphocytes within the tumor microenvironment of breast cancer via radiomics

The tumor-derived cytokine Chi3l1 induces neutrophil extracellular traps that promote T cell exclusion in triple-negative breast cancer

HER2Δ16 Engages ENPP1 to Promote an Immune-Cold Microenvironment in Breast Cancer

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