ADRB2-driven immunosuppression as a novel prognostic indicator and therapeutic avenue following neoadjuvant treatment in colorectal cancer.

Abstract

e15533 Background: Colorectal cancer (CRC) remains a major global health concern due to its high prevalence and mortality, especially in advanced stages. Despite advancements such as immune checkpoint inhibitors, resistance and tumor heterogeneity remain significant obstacles. Recent research highlights the β2-adrenergic receptor (ADRB2) signaling pathway as a crucial factor in T cell exhaustion, which weakens the immune system’s anti-tumor response. Inhibiting this pathway could restore immune function against CRC. Single-cell RNA sequencing (scRNA-seq) has enhanced understanding of the tumor microenvironment, offering new opportunities for discovering biomarkers and therapeutic targets for personalized treatment strategies. Methods: We applied scRNA-seq and bulk RNA sequencing to examine adrenergic receptor signaling in CRC, particularly before and after neoadjuvant therapy. Bioinformatics analyses identified T cells expressing ADRB2, confirmed by immunofluorescence and flow cytometry. Copy number variation (CNV) analysis detected malignant cells in the tumor microenvironment, and intercellular communication studies were conducted to explore interactions between ADRB2+ T cells and other immune cells. RNA scope was employed to map ADRB2 distribution in tissue samples. Additionally, deconvolution of TCGA data revealed important immune cell populations, helping to build a prognostic model based on adrenergic receptor signaling and therapy-induced gene expression changes. Results: The adrenergic receptor signaling pathway was notably enriched in immune cells, especially T cells. After neoadjuvant therapy, scRNA-seq revealed a significant increase in ADRB2 expression in T cells. RNA scope validated ADRB2 co-localization with T cells in CRC tissues, while flow cytometry showed increased ADRB2 expression alongside markers of T cell exhaustion and reduced immune function. CNV analysis identified malignant populations within the tumor microenvironment. Studies of intercellular interactions suggested that ADRB2+ T cells contribute to immune suppression. TCGA data deconvolution indicated that ADRB2+ T cells and CD44+ tumor cells are critical for prognosis. The resulting prognostic model, integrating adrenergic signaling and post-treatment gene expression changes, demonstrated strong predictive power for patient outcomes. Conclusions: Increased ADRB2 expression in T cells after neoadjuvant therapy in CRC correlates with poor prognosis. This positions ADRB2 as a promising prognostic biomarker and a potential therapeutic target to enhance immunotherapy effectiveness following neoadjuvant treatment. Targeting ADRB2 could offer novel approaches to alleviate immune exhaustion and improve patient outcomes.