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
基本信息
- 批准号:10727051
- 负责人:
- 金额:$ 17.35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AR geneAdrenergic AgentsAdrenergic beta-AntagonistsAffectApplications GrantsBreast Cancer PatientCD8-Positive T-LymphocytesCXC chemokine receptor 3CXCL10 geneCXCL9 geneCXCR3 geneCancer EtiologyCancer PatientCellsCessation of lifeCharacteristicsChronicChronic stressClinicalClinical TrialsCollaborationsCombined Modality TherapyCytometryDataDepartment of DefenseDevelopmentDinoprostoneDown-RegulationEnrollmentEnvironmentEpinephrineEthnic PopulationEventExhibitsFoundationsFundingFutureGene ExpressionGene Expression ProfilingGenesGrantHumanImageImmuneImmune checkpoint inhibitorImmunosuppressionImmunotherapyIncidenceInstitutionInterferon Type IIInterferon alphaInterferonsInterventionLifeLigandsLinkMalignant NeoplasmsMeasuresMediatingMediatorMentorshipMessenger RNAMetastatic MelanomaMolecularMyeloid-derived suppressor cellsNorepinephrineOutcomePathway interactionsPatient Self-ReportPatientsPre-Clinical ModelProductionPropranololProstaglandin InhibitionPsychological StressPsychosocial StressRegulatory T-LymphocyteReportingResearchResistanceRoleSamplingSignal TransductionSocial supportStressSurveysSurvival RateTestingTreatment/Psychosocial EffectsTumor BankTumor PromotionTumor TissueUnited StatesUnited States National Institutes of HealthWomanWorkadrenergic stressage groupanti-PD-L1 therapybeta-adrenergic receptorbreast cancer diagnosiscancer diagnosischemokinecohortcopingdifferential expressionepidemiology studyexperienceimmunomodulatory strategyimprovedinsightmalignant breast neoplasmmelanomamolecular markermortalitymouse modelnovelnovel therapeuticspatient responseperceived stresspharmacologicpre-clinicalprospectiveracial populationrecruitresilienceresilience scaleresistance mechanismresponsespectrographtargeted biomarkertherapeutic targettherapy developmenttherapy resistanttissue biomarkerstranscriptometranslational scientisttriple-negative invasive breast carcinomatumortumor growthtumor microenvironmenttumor progressiontumor-immune system interactionsyoung woman
项目摘要
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.
摘要
在美国,乳腺癌是最常见的癌症,也是第二大癌症原因-
所有年龄和种族/族裔群体妇女的相关死亡。免疫检查点抑制剂(ICI)
目前用于治疗三阴性乳腺癌(TNBC),占所有乳腺癌的15%。
癌症诊断,特别是在年轻女性中,是最具侵略性和致命性的亚型;然而,只有
5-20%的TNBC患者对目前的ICI单药治疗有反应,迫切需要新的策略来
帮助他人克服治疗抵抗。对ICI的抗性的一种机制是ICIs的较低表达水平。
肿瘤内趋化因子CXCL 9和CXCL 10,其对于将抗肿瘤CD 8 + T细胞吸引至肿瘤细胞至关重要。
肿瘤微环境(TME)。这项拟议中的研究将评估压力诱导的分子是否
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种情况都有关
根据流行病学研究,乳腺癌的发病率和死亡率增加,
的乳腺癌患者经历心理应激,这可以增强β-肾上腺素能信号,
这可能会降低ICIs的疗效。然而,心理社会压力在发展中的具体作用
TNBC患者中对ICI的治疗耐药性仍然未知。我们团队在临床前的研究
小鼠模型显示慢性应激及其介质,肾上腺素(EPI)和去甲肾上腺素(NE),
通过减少CD 8 + T细胞和增加免疫抑制细胞来驱动TME中的免疫抑制,
促进肿瘤生长。我们随后的研究提供了初步证据,普萘洛尔,一种泛β受体阻滞剂,
将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的慢性应激增加前列腺素E2(PGE 2)。此外,我们和其他人已经表明,PGE 2抑制
干扰素(IFN)诱导的CXCL 9和CXCL 10分泌。因此,我们假设慢性压力促进了
通过增加PGE 2和抑制IFN途径,
CXCL 9和CXCL 10的减少。我们将通过将验证过的测量结果与
前瞻性收集的心理社会压力与IFN、PGE 2、CXCL 9和CXCL 10水平以及免疫细胞
乳腺癌患者的肿瘤组织。这项研究将(i)研究一种新的机制途径
压力诱导的肿瘤进展的影响;(ii)第一个测试是否与高水平的感知压力相关
在一项使用人类乳腺癌样本的研究中,完成拟议的工作是
有望为PGE 2-IFN-趋化因子通路在应激诱导的细胞凋亡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拨款提案(例如,
R 01),以获得对这一途径的全面了解及其作为治疗靶点的潜力。
这最终可能不仅改善免疫治疗患者的临床结果,
耐药的TNBC,但也受肿瘤免疫抑制影响的其他癌症患者。
项目成果
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