Matache, A. | bioRxiv Science

bioRxiv2025

Ligand Discrimination in Immune Cells: Signal Processing Insights into Immune Dysfunction in ER+ Breast Cancer

Prior studies have shown that approximately 40% of estrogen receptor positive (ER+) breast cancer (BC) patients harbor immune signaling defects in their blood at diagnosis, and the presence of these defects predicts overall survival. Therefore, it is of interest to quantitatively characterize and measure signaling errors in immune signaling systems in these patients. Here we propose a novel approach combining communication theory and signal processing concepts to model ligand discrimination in immune cells in the peripheral blood. We use the model to measure the specificity of ligand discrimination in the presence of molecular noise by estimating the probability of error, which is the probability of making a wrong ligand identification. We apply our model to the JAK/STAT signaling pathway using high dimensional spectral flow cytometry measurements of transcription factors, including phosphorylated STATs and SMADs, in immune cells stimulated with several cytokines (IFN{gamma}, IL-2, IL-6, IL-4, and IL-10) from 19 ER+ breast cancer patients and 32 healthy controls. In addition, we apply our model to 10 healthy donor samples treated with a clinically approved JAK1/2 inhibitor. Our results show reduced ligand identification accuracy and higher levels of molecular noise in BC patients as compared to healthy controls, which may indicate altered immune signaling and the potential for immune cell dysfunction in these patients. Moreover, the inhibition of JAK1/2 produces ligand misidentification and molecular noise rates similar to, or even greater than, those observed in breast cancer. These results suggest a means to improve the use of signaling kinase inhibitor therapies by identifying patients with favorable ligand discrimination specificity profiles in their immune cells. One Sentence SummaryWe use a communication model to measure ligand discrimination errors in immune cells and molecular noise in cytokine signaling in ER+ breast cancer patients as compared to healthy controls.

cancer biology↗

bioRxiv2023

Systems profiling reveals recurrently dysregulated cytokine signaling responses in ER+ breast cancer patients' blood

Cytokines mediate cell-to-cell communication across the immune system and therefore are critical to immunosurveillance in cancer and other diseases. Several cytokines show dysregulated abundance or signaling responses in breast cancer, associated with the disease and differences in survival and progression. Cytokines operate in a coordinated manner to affect immune surveillance and regulate one another, necessitating a systems approach for a complete picture of this dysregulation. Here, we profiled cytokine signaling responses of peripheral immune cells from breast cancer patients as compared to healthy controls in a multidimensional manner across ligands, cell populations, and responsive pathways. We find alterations in cytokine responsiveness across pathways and cell types that are best defined by integrated signatures across dimensions. Alterations in the abundance of a cytokines cognate receptor do not explain differences in responsiveness. Rather, alterations in baseline signaling and receptor abundance suggesting immune cell reprogramming are associated with altered responses. These integrated features suggest a global reprogramming of immune cell communication in breast cancer. Significance StatementWhile individual cytokine responses have previously been observed to be altered in breast cancer, cytokine signaling responses are tightly interconnected in a way that has not been previously characterized. Here, we profile cytokine signaling responses and find alterations that are shared across both pathways and cell types. The signatures across these measurements better define the alterations and point to a broad immunosuppression response. HighlightsO_LIBaseline and post-stimulation cytokine signaling profiles differ between healthy donors and breast cancer patients. C_LIO_LIChanges in cytokine response are not explained by differences in abundance of the cognate receptor C_LIO_LIFeatures of signaling response and receptor abundance dysregulation are coordinated across patients C_LIO_LIIntegrated patterns of dysregulation in breast cancer patients share features of Th17 like-response as well as regulatory-like B and CD8+ T cells C_LI

cancer biology↗