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: 10570172
• 负责人: Quynh-Thu Xuan Le
• 金额: $ 57.64万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10570172
• 关键词: Affect; Algorithms; Antibodies; Blocking Antibodies; Blood; CD8-Positive T-Lymphocytes; CXCL1 gene; CXCL2 gene; Cell physiology; Cells; Chemotactic Factors; Circulation; Clinical; Data; Distant Metastasis; Endothelium; Exclusion; Fractionated radiotherapy; Galectin 1; Genetic; Growth; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Human; Human Papillomavirus; Hypoxia; IL8RB gene; Immune; Immune system; Immunosuppression; Link; Literature; Lung; Malignant Neoplasms; Measures; Mediating; Mediator; Metastatic Neoplasm to the Lung; Modeling; Mus; Myeloid Cells; Myeloid-derived suppressor cells; Neoplasm Metastasis; Pathway interactions; Patients; Peripheral; Phenotype; Play; Primary Neoplasm; Prognosis; Progression-Free Survivals; Proteins; RANTES; Radiation; Radiation therapy; Role; Shapes; Site; Stains; System; T-Cell Depletion; T-Lymphocyte; Testing; Translating; Treatment Failure; Tumor Promotion; Tumor-Derived; angiogenesis; anti-PD-1; anti-PD1 antibodies; anti-PD1 therapy; cancer cell; checkpoint therapy; chemokine; chemoradiation; comparative efficacy; improved; inhibitor; malignant mouth neoplasm; migration; mouse model; neoplastic cell; novel therapeutics; overexpression; programmed cell death protein 1; recruit; response; small molecule inhibitor; success; tumor; tumor growth; tumor microenvironment

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.

摘要 头颈部鳞状细胞癌(HNSCC)是全球第9大最常见的癌症。研究表明， 肿瘤对宿主免疫系统的抑制是HNSCC进展和转移的关键。 肿瘤分泌因子直接影响髓系抑制细胞(MDSC)的扩张，MDSC具有 成为癌症免疫抑制的最重要的介体。MDSC不仅通过以下途径促进肿瘤生长 抑制肿瘤内的T细胞，但也通过促进血管生成和转移前促进转移 生态位形成。肿瘤周围和微环境中存在扩张的多药耐药干细胞。 与明确治疗的预后较差和对抗PD1免疫检查点的反应较少有关 HNSCC的治疗。此外，RT本身已被证明系统性地提高MDSC水平。因此， 研究促进MDSC扩展、招募和功能的因素是开发新的 治疗。我们已经证明Galectin-1(Galectin-1，Gal-1)是由缺氧和/或RT诱导的HNSCC及其 肿瘤间质中高表达与预后不良相关。我们有数据表明Gal-1 表达肿瘤的肿瘤含有高水平的局部和系统MDSC，并且Gal-1被阻断(遗传或与 抗体)在整个过程中显著减少了MDSC的数量，与其对T细胞的影响无关。此外， GAL-1阻断可减少转移，减少MDSC向转移部位的募集。尽管广泛 文献支持Gal1‘S对T细胞的作用，很少有研究评价其与骨髓间充质干细胞的关系。基座 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向 原发肿瘤同时通过MDSC驱动转移前生态位的形成促进转移。 此外，RT诱导Gal-1分泌可能导致接受RT的患者全身性MDSC较高。 因此，阻断Gal-1可以减轻局部和全身MDSC的负荷，增强肿瘤反应 接受放射治疗和免疫检查点治疗。我们将以以下具体目标来检验这一假设：(1) 确定Gal-1是否介导了RT提高肿瘤和全系统MDSC水平的作用 (2)识别介导Gal-1‘S诱导骨髓间充质干细胞的宿主和肿瘤细胞依赖因素 肿瘤微环境的全系统扩增和募集；(3)确定MDSC是否介导 Gal-1‘S对Gal-1+HNSCC转移的影响及阻断CXCR2是否能减少远处转移 (4)确定CXCR2抑制与Gal-1阻断联合RT和PD1是否同样有效 HNSCC中的抗体以及参与这些治疗的免疫细胞的特征。而最优Gal-1 靶向正在开发中，临床级别的CXCR2抑制剂已经存在，并正在进行两种癌症的试验 以及非癌症的情况。如果我们的研究成功，将为CXCR2抑制剂与 Gal-1高表达HNSCC的RT和抗PD1治疗