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）是全球第九大常见癌症。研究表明 肿瘤诱导的宿主免疫系统抑制对HNSCC进展和转移至关重要。 肿瘤分泌因子直接影响髓源性抑制细胞（MDSC）的扩增， 成为癌症免疫抑制的最前沿介质。MDSC不仅促进肿瘤生长， 抑制肿瘤内的T细胞，而且还通过增强血管生成和转移前 生态位形成在肿瘤周围和肿瘤微环境中存在扩增的MDSC， 与确定性治疗的预后较差和对抗PD 1免疫检查点的应答较低相关 治疗HNSCC。此外，RT本身已被证明可以系统地增加MDSC水平。因此，我们认为， 调查促进MDSC扩展、招募和功能的因素是开发新的 治疗我们先前已经表明，半乳糖凝集素-1（Gal-1）在HNSCC中是由缺氧和/或RT诱导的，并且其 肿瘤间质中的高表达与不良预后相关。我们有数据表明Gal-1 表达MDSC的肿瘤具有高水平的局部和全身MDSC，并且Gal-1阻断（遗传或与 抗体）实质上减少了整个MDSC的数量，与其对T细胞的作用无关。此外，委员会认为， Gal-1阻断导致较少的转移和较少的MDSC募集到转移部位。尽管进行了广泛 尽管文献支持Gal-1对T细胞的作用，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向 同时通过MDSC驱动的转移前小生境形成促进转移。 此外，RT诱导Gal-1分泌可能导致接受RT的患者中观察到的更高的全身MDSC。 因此，Gal-1阻断可降低局部和全身MDSC负荷并增强肿瘤反应 RT和免疫检查点疗法的效果我们将以下列具体目标来检验这一假设：（1） 确定Gal-1是否介导RT对增加肿瘤和全系统MDSC水平的影响 （2）探讨Gal-1诱导MDSC的宿主和肿瘤细胞相关因子 （3）为了确定MDSC是否介导了肿瘤细胞的增殖和向肿瘤微环境的募集， Gal-1对转移的影响以及CXCR 2阻断是否减少Gal-1+ HNSCC中的远处转移，以及 (4)确定CXCR 2抑制与RT和PD 1联合使用时是否与Gal-1阻断一样有效 HNSCC中的抗体并表征参与这些治疗的免疫细胞。而最佳Gal-1 靶向正在开发中，临床级CXCR 2抑制剂存在，并正在两种癌症的试验中进行测试 和非癌症条件。我们的研究，如果成功，将提供整合CXCR 2抑制剂与 在Gal-1过表达的HNSCC中的RT和抗PD 1治疗。