The role of Galectin-1 in shaping the immune suppressive landscape in head and neck cancer
Galectin-1 在塑造头颈癌免疫抑制景观中的作用
基本信息
- 批准号:10570172
- 负责人:
- 金额:$ 57.64万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-14 至 2026-02-28
- 项目状态:未结题
- 来源:
- 关键词:AffectAlgorithmsAntibodiesBlocking AntibodiesBloodCD8-Positive T-LymphocytesCXCL1 geneCXCL2 geneCell physiologyCellsChemotactic FactorsCirculationClinicalDataDistant MetastasisEndotheliumExclusionFractionated radiotherapyGalectin 1GeneticGrowthHead and Neck CancerHead and Neck Squamous Cell CarcinomaHumanHuman PapillomavirusHypoxiaIL8RB geneImmuneImmune systemImmunosuppressionLinkLiteratureLungMalignant NeoplasmsMeasuresMediatingMediatorMetastatic Neoplasm to the LungModelingMusMyeloid CellsMyeloid-derived suppressor cellsNeoplasm MetastasisPathway interactionsPatientsPeripheralPhenotypePlayPrimary NeoplasmPrognosisProgression-Free SurvivalsProteinsRANTESRadiationRadiation therapyRoleShapesSiteStainsSystemT-Cell DepletionT-LymphocyteTestingTranslatingTreatment FailureTumor PromotionTumor-Derivedangiogenesisanti-PD-1anti-PD1 antibodiesanti-PD1 therapycancer cellcheckpoint therapychemokinechemoradiationcomparative efficacyimprovedinhibitormalignant mouth neoplasmmigrationmouse modelneoplastic cellnovel therapeuticsoverexpressionprogrammed cell death protein 1recruitresponsesmall molecule inhibitorsuccesstumortumor growthtumor microenvironment
项目摘要
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the 9th most common cancer globally. Studies have shown
that tumor-induced suppression of the host immune system is critical to HNSCC progression and metastasis.
Tumor secreted factors directly influence the expansion of myeloid-derived suppressor cells (MDSC), which have
emerged as forefront mediators of cancer immune suppression. MDSC not only promote tumor growth by
suppressing T cells within the tumor, but also facilitate metastasis by enhancing angiogenesis and pre-metastatic
niche formation. The presence of expanded MDSC peripherally and within the tumor microenvironment has been
associated with worse prognosis with definitive treatment and less response to anti-PD1 immune checkpoint
therapy in HNSCC. Moreover, RT itself has been shown to increase MDSC level systemically. Therefore,
investigating factors that facilitate MDSC expansion, recruitment and function is integral to developing novel
therapies. We have previously shown that Galectin-1 (Gal-1) is induced by hypoxia and/or RT in HNSCC and its
elevated expression in the tumor stroma correlated with poor prognosis. We have data indicating that Gal-1
expressing tumors harbor high levels of local and systemic MDSC, and that Gal-1 blockade (genetically or with
antibodies) substantially reduced the number of MDSC throughout, independent of its effect on T cells. Moreover,
Gal-1 blockade led to fewer metastases and less MDSC recruitment to metastatic sites. Despite extensive
literature supporting Gal-1’s effect on T cells, very few studies have evaluated its relationship with MDSC. Based
on our preliminary data, we hypothesize that tumor secreted Gal-1 can directly affect MDSC recruitment to the
primary tumor while simultaneously promote metastases through MDSC driven pre-metastatic niche formation.
In addition, RT-induction of Gal-1 secretion may lead to higher systemic MDSC noted in patients receiving RT.
Therefore, Gal-1 blockade can decrease both local and systemic MDSC burden and enhance tumor response
to both RT and immune check point therapy. We will test this hypothesis with the following specific aims: (1) To
determine whether Gal-1 mediates the effect of RT on increasing MDSC level in the tumor and systemwide in
HNSCC; (2) To discern the host versus tumor cell dependent factors mediating Gal-1’s induction of MDSC
expansion systemwide and recruitment to the tumor microenvironment; (3) To determine whether MDSC mediate
Gal-1’s effect on metastases and whether CXCR2 blockade decrease distant metastasis in Gal-1+ HNSCC, and
(4) To determine whether CXCR2 inhibition is as effective as Gal-1 blockade when combined with RT and PD1
antibody in HNSCC and to characterize the immune cells involved in these treatments. While optimal Gal-1
targeting is being developed, clinical grade CXCR2 inhibitors exist and are being tested in trials for both cancer
and non-cancer conditions. Our studies, if successful, will provide rationales for integrating CXCR2 inhibitor with
RT and anti-PD1 therapy in Gal-1 overexpressing HNSCC.
抽象的
头颈鳞状细胞癌 (HNSCC) 是全球第九大常见癌症。研究表明
肿瘤诱导的宿主免疫系统抑制对于 HNSCC 的进展和转移至关重要。
肿瘤分泌因子直接影响骨髓源性抑制细胞(MDSC)的扩增,
成为癌症免疫抑制的前沿介质。 MDSC不仅通过促进肿瘤生长
抑制肿瘤内的 T 细胞,还通过增强血管生成和转移前促进转移
利基形成。外周和肿瘤微环境内存在扩展的 MDSC
与根治性治疗的预后较差以及抗 PD1 免疫检查点反应较差相关
HNSCC 的治疗。此外,RT 本身已被证明可以系统性地提高 MDSC 水平。所以,
研究促进 MDSC 扩展、招募和功能的因素对于开发新型药物至关重要
疗法。我们之前已经证明,半乳糖凝集素-1 (Gal-1) 在 HNSCC 及其相关疾病中是由缺氧和/或放疗诱导的。
肿瘤基质中表达升高与不良预后相关。我们有数据表明 Gal-1
表达肿瘤具有高水平的局部和全身 MDSC,并且 Gal-1 阻断(遗传或通过
抗体)显着减少了整个过程中 MDSC 的数量,与其对 T 细胞的影响无关。而且,
Gal-1 阻断导致转移灶减少以及转移部位的 MDSC 募集减少。尽管广泛
尽管有文献支持 Gal-1 对 T 细胞的影响,但很少有研究评估其与 MDSC 的关系。基于
根据我们的初步数据,我们假设肿瘤分泌的 Gal-1 可以直接影响 MDSC 募集到
原发肿瘤,同时通过 MDSC 驱动的转移前生态位形成促进转移。
此外,RT 诱导的 Gal-1 分泌可能导致接受 RT 的患者出现更高的全身性 MDSC。
因此,Gal-1阻断可以减少局部和全身MDSC负荷并增强肿瘤反应
RT 和免疫检查点治疗。我们将通过以下具体目标来检验这一假设:(1)
确定 Gal-1 是否介导 RT 对肿瘤和全身 MDSC 水平增加的影响
颈椎间盘突出症; (2) 辨别介导 Gal-1 诱导 MDSC 的宿主与肿瘤细胞依赖性因素
全系统扩张并招募到肿瘤微环境; (3)判断MDSC是否介导
Gal-1 对转移的影响以及 CXCR2 阻断是否会减少 Gal-1+ HNSCC 的远处转移,以及
(4) 确定 CXCR2 抑制与 RT 和 PD1 联合使用时是否与 Gal-1 阻断一样有效
HNSCC 中的抗体并表征这些治疗中涉及的免疫细胞。虽然最佳 Gal-1
靶向治疗正在开发中,临床级 CXCR2 抑制剂已经存在,并且正在针对这两种癌症进行试验
和非癌症状况。我们的研究如果成功,将为将 CXCR2 抑制剂与
Gal-1 过表达 HNSCC 中的 RT 和抗 PD1 治疗。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Quynh-Thu Xuan Le其他文献
Quynh-Thu Xuan Le的其他文献
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{{ truncateString('Quynh-Thu Xuan Le', 18)}}的其他基金
2022 Nasopharyngeal Carcinoma Gordon Research Conference
2022年鼻咽癌戈登研究会议
- 批准号:
10427491 - 财政年份:2022
- 资助金额:
$ 57.64万 - 项目类别:
Project 2: ALDH3A1 Activation for Radioprotection of Salivary Glands and Other Head and Neck Epithelial Tissues
项目2:ALDH3A1激活对唾液腺和其他头颈上皮组织的辐射防护
- 批准号:
10334200 - 财政年份:2022
- 资助金额:
$ 57.64万 - 项目类别:
Precision imaging for risk stratification and personalized therapy of oropharyngeal cancer
口咽癌风险分层和个性化治疗的精准成像
- 批准号:
10659176 - 财政年份:2022
- 资助金额:
$ 57.64万 - 项目类别:
Project 2: ALDH3A1 Activation for Radioprotection of Salivary Glands and Other Head and Neck Epithelial Tissues
项目2:ALDH3A1激活对唾液腺和其他头颈上皮组织的辐射防护
- 批准号:
10707889 - 财政年份:2022
- 资助金额:
$ 57.64万 - 项目类别:
Precision imaging for risk stratification and personalized therapy of oropharyngeal cancer
口咽癌风险分层和个性化治疗的精准成像
- 批准号:
10445148 - 财政年份:2022
- 资助金额:
$ 57.64万 - 项目类别:
The role of Galectin-1 in shaping the immune suppressive landscape in head and neck cancer
Galectin-1 在塑造头颈癌免疫抑制景观中的作用
- 批准号:
10392852 - 财政年份:2021
- 资助金额:
$ 57.64万 - 项目类别:
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