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

摘要 在美国，乳腺癌是最常见的癌症，也是第二大致癌原因。 所有年龄段和种族/族裔群体的妇女的相关死亡。免疫检查点抑制物(ICIS)是 目前用于治疗三阴性乳腺癌(TNBC)，占所有乳房的15% 癌症诊断，特别是在年轻女性中，是最具侵袭性和致命性的亚型；然而，只有 5%-20%的TNBC患者对目前的ICI单一疗法有反应，迫切需要新的策略来 帮助他人克服治疗耐药性。ICIS耐药的一个机制是低水平的表达 肿瘤内趋化因子CXCL9和CXCL10对吸引抗肿瘤CD8+T细胞进入肿瘤至关重要 肿瘤微环境。这项拟议的研究将评估应激诱导的分子 这些途径与这些趋化因子的表达有关。心理社会压力与这两个因素有关 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 的乳腺癌患者经历心理压力，这可以增强β-肾上腺素能信号， 潜在地降低了ICIS的效力。然而，心理社会压力在发育中的具体作用 TNBC患者对ICIS耐药的原因尚不清楚。我们团队在临床前的研究 小鼠模型已经表明，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细胞和增加免疫抑制细胞来驱动TME中的免疫抑制，从而 促进肿瘤生长。我们随后的研究提供了初步证据，普萘洛尔是一种泛β阻滞剂， 将转移性黑色素瘤患者对ICIS的反应从30-40%提高到78%。我们还发现， 通过EPI的慢性应激会增加前列腺素E2(PGE2)。此外，我们和其他人已经证明PGE2抑制 干扰素诱导CXCL9和CXCL10的分泌。因此，我们假设慢性压力会促进 通过增加PGE2和抑制干扰素途径抑制TNBC的免疫抑制，最终导致 CXCL9和CXCL10的减少。我们将通过关联经过验证的测量结果来检验我们的假设 预期收集的心理社会应激与干扰素、前列腺素E_2、CXCL9和CXCL10及免疫细胞水平的关系 乳腺癌患者的肿瘤组织。这项拟议的研究将(I)研究一种新的机制途径 以及(Ii)第一个测试感知到的高水平的压力是否与 在一项使用人类乳腺癌样本的研究中使用了免疫抑制。拟议工作的完成日期为 有望为PGE2-干扰素-趋化因子途径在应激诱导中的作用提供重要的见解 TME中的免疫抑制，这将使我们能够开发未来具有竞争力的NIH赠款提案(例如， R01)，以全面了解这一途径及其作为治疗靶点的潜力。 这最终可能导致不仅接受免疫治疗的患者的临床结果有所改善- 耐药的TNBC，但也有其他癌症患者受到肿瘤免疫抑制的影响。

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.