Identifying the role of interferon and interferon-regulated chemokines in stress-induced immunosuppression in triple negative breast cancer

确定干扰素和干扰素调节的趋化因子在三阴性乳腺癌应激诱导的免疫抑制中的作用

• 批准号: 10727051
• 负责人: Shipra Gandhi
• 金额: $ 17.35万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10727051
• 关键词: AR gene; Adrenergic Agents; Adrenergic beta-Antagonists; Affect; Applications Grants; Breast Cancer Patient; CD8-Positive T-Lymphocytes; CXC chemokine receptor 3; CXCL10 gene; CXCL9 gene; CXCR3 gene; Cancer Etiology; Cancer Patient; Cells; Cessation of life; Characteristics; Chronic; Chronic stress; Clinical; Clinical Trials; Collaborations; Combined Modality Therapy; Cytometry; Data; Department of Defense; Development; Dinoprostone; Down-Regulation; Enrollment; Environment; Epinephrine; Ethnic Population; Event; Exhibits; Foundations; Funding; Future; Gene Expression; Gene Expression Profiling; Genes; Grant; Human; Image; Immune; Immune checkpoint inhibitor; Immunosuppression; Immunotherapy; Incidence; Institution; Interferon Type II; Interferon alpha; Interferons; Intervention; Life; Ligands; Link; Malignant Neoplasms; Measures; Mediating; Mediator; Mentorship; Messenger RNA; Metastatic Melanoma; Molecular; Myeloid-derived suppressor cells; Norepinephrine; Outcome; Pathway interactions; Patient Self-Report; Patients; Pre-Clinical Model; Production; Propranolol; Prostaglandin Inhibition; Psychological Stress; Psychosocial Stress; Regulatory T-Lymphocyte; Reporting; Research; Resistance; Role; Sampling; Signal Transduction; Social support; Stress; Surveys; Survival Rate; Testing; Treatment/Psychosocial Effects; Tumor Bank; Tumor Promotion; Tumor Tissue; United States; United States National Institutes of Health; Woman; Work; adrenergic stress; age group; anti-PD-L1 therapy; beta-adrenergic receptor; breast cancer diagnosis; cancer diagnosis; chemokine; cohort; coping; differential expression; epidemiology study; experience; immunomodulatory strategy; improved; insight; malignant breast neoplasm; melanoma; molecular marker; mortality; mouse model; novel; novel therapeutics; patient response; perceived stress; pharmacologic; pre-clinical; prospective; racial population; recruit; resilience; resilience scale; resistance mechanism; response; spectrograph; targeted biomarker; therapeutic target; therapy development; therapy resistant; tissue biomarkers; transcriptome; translational scientist; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumor progression; tumor-immune system interactions; young woman

ABSTRACT In the United States, breast cancer is the most commonly diagnosed cancer and second leading cause of cancer- related deaths among women of all ages and racial/ethnic groups. Immune checkpoint inhibitors (ICIs) are currently being used for the treatment of triple negative breast cancer (TNBC), which comprises 15% of all breast cancer diagnoses, especially in younger women, and is the most aggressive and lethal subtype; however, only 5-20% of TNBC patients are responsive to current ICI monotherapy and new strategies are urgently needed to help others overcome treatment resistance. One mechanism of resistance to ICIs is lower expression levels of intratumoral chemokines CXCL9 and CXCL10 that are essential for attracting anti-tumor CD8+ T cells to the tumor microenvironment (TME). The proposed research will evaluate whether stress-induced molecular pathways are linked to the expression of these chemokines. Psychosocial stress is associated with both increased incidence and mortality of breast cancer according to epidemiological studies, and between 30-75% of breast cancer patients experience psychological stress, which can enhance β-adrenergic signaling, potentially reducing the efficacy of ICIs. However, the specific role of psychosocial stress in the development of treatment resistance to ICIs among TNBC patients remains unknown. Our team's research in preclinical mouse models has shown that chronic stress and its mediators, epinephrine (EPI) and norepinephrine (NE), drive immunosuppression in the TME by decreasing CD8+ T cells and increasing immunosuppressive cells, thus promoting tumor growth. Our subsequent study provided preliminary evidence that propranolol, a pan-β-blocker, improves responses to ICIs in patients with metastatic melanoma from 30-40% to 78%. We also found that chronic stress via EPI increases prostaglandin E2 (PGE2). Further, we and others have shown that PGE2 inhibits interferon (IFN)-induced CXCL9 and CXCL10 secretion. Thus, we hypothesize that chronic stress promotes immunosuppression in TNBC by increasing PGE2 and inhibiting IFN pathways, which ultimately leads to decreases in CXCL9 and CXCL10. We will test our hypothesis by correlating validated measures of psychosocial stress with levels of IFN, PGE2, CXCL9 and CXCL10, and immune cells in prospectively collected tumor tissues from breast cancer patients. The proposed study will (i) investigate a novel mechanistic pathway of stress-induced tumor progression and (ii) be the first to test if high levels of perceived stress are associated with immunosuppression in a study using human breast cancer samples. Completion of the proposed work is expected to provide crucial insights into the role of the PGE2-IFN-chemokine pathway in stress-induced immunosuppression in the TME, which will allow us to develop future competitive NIH grant proposals (e.g., R01) to obtain a comprehensive understanding of this pathway and its potential to be therapeutically targeted. This could eventually lead to improved clinical outcomes for not only patients with immunotherapy- resistant TNBC, but also other cancer patients affected by tumor immunosuppression.

抽象的 在美国，乳腺癌是最常见的癌症和癌症的第二主要原因 各个年龄段和种族/族裔妇女之间的相关死亡。免疫检查点抑制剂（ICI）为 目前用于治疗三重阴性乳腺癌（TNBC），占所有乳房的15％ 癌症诊断，尤其是在年轻女性中，是最具侵略性和致命的亚型；但是，只有 5-20％的TNBC患者对当前的ICI单一疗法有反应，并且迫切需要新的策略 帮助其他人克服抗药性。对ICI的抵抗的一种机制是较低的表达水平 肿瘤内趋化因子CXCL9和CXCL10对于吸引抗肿瘤CD8+ T细胞至关重要 肿瘤微环境（TME）。拟议的研究将评估应力诱导的分子 途径与这些趋化因子的表达有关。社会心理压力都与 根据流行病学研究，乳腺癌的发病率和死亡率增加，在30-75％之间 乳腺癌患者的心理压力可以增强β-肾上腺素信号传导， 潜在地降低ICI的效率。但是，社会心理压力在发展中的具体作用 TNBC患者对ICI的治疗耐药性仍然未知。我们团队在临床前的研究 小鼠模型表明，慢性应激及其介体肾上腺素（EPI）和去甲肾上腺素（NE）， 通过减少CD8+ T细胞并增加免疫抑制细胞，驱动TME的免疫抑制，从而驱动免疫抑制 促进肿瘤生长。我们随后的研究提供了初步证据，表明PAN-β受体阻滞剂普萘洛尔 转移性黑色素瘤患者对ICI的反应从30-40％提高到78％。我们还发现 通过EPI的慢性应激增加了前列腺素E2（PGE2）。此外，我们和其他人表明PGE2抑制了 干扰素（IFN）诱导的CXCL9和CXCL10分泌。这，我们假设慢性压力会促进 通过增加PGE2并抑制IFN途径，在TNBC中进行免疫抑制，最终导致 减少CXCL9和CXCL10。我们将通过将经过验证的措施的措施来检验我们的假设 IFN，PGE2，CXCL9和CXCL10水平的社会心理应力以及前瞻性收集的免疫电池 乳腺癌患者的肿瘤组织。拟议的研究将（i）研究一种新的机械途径 压力诱导的肿瘤进展和（ii）是第一个测试是否相关的高水平的应激 在一项使用人类乳腺癌样品的研究中进行免疫抑制。拟议工作的完成是 预计将提供有关PGE2-IFN-化学途径在应力诱导中的作用的关键见解 TME中的免疫抑制，这将使我们能够制定未来的竞争性NIH赠款建议（例如， R01）为了获得对该途径及其受热靶向的潜力的全面理解。 最终，这不仅可以改善免疫疗法患者的临床结局。 抗性TNBC，以及其他受肿瘤免疫抑制影响的癌症患者。