TARGETING INOS TO INHIBIT MYELOID-DERIVED SUPPRESSOR CELLS (MDSC) IN MELANOMA

靶向 INOS 抑制黑色素瘤中的骨髓源性抑制细胞 (MDSC)

• 批准号: 8920510
• 负责人: Andrew Sikora
• 金额: $ 13.49万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-08 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8920510
• 关键词: Ablation; Address; Affect; Animals; Area; Biometry; Bone Marrow; CD8B1 gene; Cancer Biology; Cancer Immunology Science; Cancer Patient; Cell Count; Cell Culture System; Cell Differentiation process; Cells; Chemicals; Clinical Research; Clinical Trials; Critiques; Cutaneous Melanoma; Data; Data Analyses; Development; Development Plans; Down-Regulation; Environment; Enzymes; Experimental Designs; Funding; Generations; Genetic; Goals; Grant; Growth Factor; Homing; Human; ITGAM gene; Immune; Immune response; Immunization; Immunology; Immunosuppression; Immunosuppressive Agents; Immunotherapy; In Vitro; Infection; Infiltration; Inflammation; Inflammatory; Institution; Knockout Mice; Lead; Leukocytes; Lysine; Maintenance; Malignant Neoplasms; Mediating; Mediator of activation protein; Melanoma Cell; Mentors; Mentorship; Modeling; Molecular; Mus; Myelogenous; Myeloid Cells; Myeloproliferative disease; Natural Killer Cells; Nitric Oxide; Nitric Oxide Synthetase Inhibitor; Peptides; Physicians; Play; Production; Publications; Publishing; Recruitment Activity; Relative (related person); Research; Resistance; Role; STAT3 gene; Scientist; Secure; Serum; Shock; Skin Cancer; Solid Neoplasm; Spleen; Splenocyte; Suppressor-Effector T-Lymphocytes; T cell response; T-Lymphocyte; Testing; Transgenic Organisms; Translations; Vaccination; Vascular Endothelial Growth Factors; Work; Writing; base; cancer immunotherapy; career; career development; chemokine; clinical material; cytokine; design; experience; human NOS2A protein; improved; in vitro testing; lymph nodes; melanoma; migration; mouse model; neoplastic cell; novel; novel strategies; patient population; programs; response; skills; small molecule; sound; trafficking; tumor; tumor progression; vaccine efficacy

DESCRIPTION (provided by applicant): Myeloid-derived suppressor cells (MDSC) are immature myeloid cells described in both tumor-bearing mice and human cancer patients, which play an increasingly recognized role in cancer maintenance, progression, and resistance to immunotherapy. MDSC infiltrate solid tumors, including coetaneous melanoma, and potently inhibit anti-tumor T cell responses through a variety of mechanisms including production of nitric oxide (NO) by inducible nitric oxide synthase (iNOS). While iNOS/NO have not previously been shown to regulate MDSC development, persistence, or localization within the tumor-bearing host, the well-known associations of iNOS with cancer, infection, shock, and other inflammatory states associated with MDSC accumulation make this an attractive hypothesis. Our preliminary data demonstrate that mice bearing syngeneic B16 or MT-RET melanomas accumulate splenic and tumor-infiltrating GR-1+CD11b+ MDSC, and experience a decline in splenic CD4+ and CD8+ T cells. Treatment with the small molecule iNOS inhibitor N6(1-iminoethyl)-L-lysine-dihydrochloride (L-NIL) decreases MDSC infiltration in tumor and spleen, reverses the tumor-mediated decrease in CD4+ and CD8+ splenocytes, and enhances the number of tumor-infiltrating CD4+ and CD8+ T cells. L-nil treatment was also associated with down regulation of activated STAT3 in the tumor, and normalization of elevated levels of VEGF and other inflammatory cytokines observed in sera of tumor-bearing mice. Serum VEGF levels were also suppressed, intratumoral MDSC infiltration reduced, and T cell numbers normalized in tumor-bearing iNOS-/- "knockout" mice, suggesting that host-derived iNOS plays a role in MDSC recruitment and migration. Together, these data suggest that MDSC recruitment and trafficking are controlled by cross-talk in which iNOS expression by tumor-infiltrating myeloid cells, melanoma cells, or both is required for release of soluble factors from the tumor which recruit additional MDSC from the bone marrow and drive their infiltration into the tumor. We further hypothesize that targeted inhibition of iNOS with small-molecule chemical antagonists will enhance the response to anti-tumor vaccination by suppressing the recruitment and suppressive capacity of intratumoral MDSC. In this proposal we aim to characterize the effect of iNOS inhibition on tumor-secreted factors responsible for recruitment and intratumoral homing of MDSC in syngeneic transplantable and spontaneous tumor models. We will seek to determine whether the effects of iNOS inhibition on production, by tumor and myeloid cells, of cytokines known to regulate MDSC are mediated by changes in STAT3 activation. We will determine whether iNOS inhibition decreases intratumoral MDSC numbers by affecting their trafficking, survival, or differentiation, or through a combination of these mechanisms. Finally, we will use a well-established model of adoptive CD8+ T cell transfer and anti-tumor vaccination to determine whether targeted iNOS inhibition boosts the number, effector function, and anti-tumor efficacy of vaccine-induced CD8+ CTL. The above project will be carried out in the context of a comprehensive, mentored career development plan leading to scientific independence. A team of outstanding mentors will provide critical guidance in every aspect of the candidate's scientific development, from hands-on critique of experimental design and data analysis, to publication of results, to acquisition of lab management and grant-writing skills which will lead to independent funding. These personal interactions will be supplemented by formal class work addressing specific areas targeted for improvement (biostatistics, clinical research skills and translation of basic findings to clinical trials). As the candidate is a physician-scientist with access to unique patient populations and clinical material, special emphasis has been placed on providing didactic background and supplemental mentorship in clinical research. The candidate has the benefit of a first class research environment in which immunology and cancer biology are centers of excellence within the institution, and already has secured the confidence and support of his department and the institution. His immediate goal of carrying out and publishing the research proposed in this application will significantly enhance our understanding of the relationship between inflammation and tumor-mediated immunosuppression, and provide a sound platform for establishing an independent research career in cancer immunology and translational cancer biology.

描述（由申请人提供）：髓源性抑制细胞（MDSC）是在荷瘤小鼠和人类癌症患者中描述的未成熟髓样细胞，其在癌症维持、进展和免疫治疗抗性中发挥越来越多的作用。MDSC浸润实体瘤，包括共时黑色素瘤，并通过多种机制有效地抑制抗肿瘤T细胞应答，包括通过诱导型一氧化氮合酶（iNOS）产生一氧化氮（NO）。虽然iNOS/NO以前没有显示出调节MDSC的发展，持久性，或在荷瘤宿主中的定位，但众所周知的iNOS与癌症，感染，休克和与MDSC积累相关的其他炎症状态的关联使其成为一个有吸引力的假设。我们的初步数据表明，携带同基因B16或MT-RET黑色素瘤的小鼠在脾脏和肿瘤浸润性GR-1+ CD 11b + MDSC中积累，并经历脾脏CD 4+和CD 8 + T细胞的下降。使用小分子iNOS抑制剂N6（1-亚氨基乙基）-L-赖氨酸二盐酸盐（L-NIL）治疗可减少肿瘤和脾脏中MDSC的浸润，逆转肿瘤介导的CD 4+和CD 8+脾细胞减少，并增加肿瘤浸润的数量CD 4+和CD 8 + T细胞。L-nil治疗还与肿瘤中活化的STAT 3的下调以及荷瘤小鼠血清中观察到的VEGF和其他炎性细胞因子水平升高的正常化相关。血清VEGF水平也受到抑制，肿瘤内MDSC浸润减少，T细胞数量正常化，在荷瘤iNOS-/-“敲除”小鼠，表明宿主来源的iNOS在MDSC募集和迁移中发挥作用。总之，这些数据表明MDSC募集和运输受串扰控制，其中肿瘤浸润性骨髓细胞、黑素瘤细胞或两者的iNOS表达是从肿瘤释放可溶性因子所需的，所述可溶性因子从骨髓募集额外的MDSC并驱动它们浸润到肿瘤中。我们进一步假设，用小分子化学拮抗剂靶向抑制iNOS将通过抑制肿瘤内MDSC的募集和抑制能力来增强对抗肿瘤疫苗接种的反应。在这个建议中，我们的目标是表征iNOS抑制肿瘤分泌的因素负责招聘和肿瘤内归巢的MDSC在同基因移植和自发性肿瘤模型的影响。我们将试图确定iNOS抑制对肿瘤和骨髓细胞产生已知调节MDSC的细胞因子的影响是否是由STAT 3激活的变化介导的。我们将确定iNOS抑制是否通过影响其运输、存活或分化或通过这些机制的组合来减少瘤内MDSC数量。最后，我们将使用过继性CD 8 + T细胞转移和抗肿瘤疫苗接种的成熟模型来确定靶向iNOS抑制是否增加疫苗诱导的CD 8 + CTL的数量、效应子功能和抗肿瘤功效。上述项目将在一个全面的、有指导的职业发展计划的背景下实施，以实现科学独立。一个优秀的导师团队将在候选人的科学发展的各个方面提供关键的指导，从实验设计和数据分析的实践批判，结果的出版，以获得实验室管理和赠款写作技能，这将导致独立的资金。这些个人互动将通过正式的课堂作业来补充，这些课堂作业将针对特定领域进行改进（生物统计学，临床研究技能和将基本发现翻译为临床试验）。由于候选人是一名医生科学家，可以接触到独特的患者群体和临床材料，因此特别强调在临床研究中提供教学背景和补充指导。候选人享有一流的研究环境，其中免疫学和癌症生物学是该机构的卓越中心，并且已经获得了他所在部门和机构的信任和支持。他的近期目标是开展和发表本申请中提出的研究，这将显著增强我们对炎症与肿瘤介导的免疫抑制之间关系的理解，并为建立癌症免疫学和转化癌症生物学的独立研究事业提供良好的平台。

项目成果

Reduced impact of nodal metastases as a prognostic factor for tonsil cancer in the HPV era.

在 HPV 时代，淋巴结转移作为扁桃体癌预后因素的影响减少。

• DOI: 10.1007/s00405-013-2796-2
• 发表时间: 2014
• 期刊: European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery
• 作者: Vila,PeterM;Stucken,ChazL;Morris,LucGT;Posner,MarshallR;Genden,EricM;Boffetta,Paolo;Sikora,AndrewG
• 通讯作者: Sikora,AndrewG

Counseling the patient with potentially HPV-related newly diagnosed head and neck cancer.

• DOI: 10.1007/s11912-013-0375-8
• 发表时间: 2014-03
• 期刊: CURRENT ONCOLOGY REPORTS
• 影响因子: 4.7
• 作者: Finnigan, John P., Jr.;Sikora, Andrew G.
• 通讯作者: Sikora, Andrew G.

Chemoradiotherapy-induced upregulation of PD-1 antagonizes immunity to HPV-related oropharyngeal cancer.

• DOI: 10.1158/0008-5472.can-14-1913
• 发表时间: 2014-12-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Parikh F;Duluc D;Imai N;Clark A;Misiukiewicz K;Bonomi M;Gupta V;Patsias A;Parides M;Demicco EG;Zhang DY;Kim-Schulze S;Kao J;Gnjatic S;Oh S;Posner MR;Sikora AG
• 通讯作者: Sikora AG

TGFβ receptor 1: an immune susceptibility gene in HPV-associated cancer.

• DOI: 10.1158/0008-5472.can-14-0602-t
• 发表时间: 2014-12-01
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Levovitz C;Chen D;Ivansson E;Gyllensten U;Finnigan JP;Alshawish S;Zhang W;Schadt EE;Posner MR;Genden EM;Boffetta P;Sikora AG
• 通讯作者: Sikora AG

Prediagnostic serum levels of inflammatory biomarkers are correlated with future development of lung and esophageal cancer.

炎症生物标志物的诊断前血清水平与肺癌和食道癌的未来发展相关。

• DOI: 10.1111/cas.12485
• 发表时间: 2014
• 期刊: Cancer science
• 影响因子: 5.7
• 作者: Keeley,BriezeR;Islami,Farhad;Pourshams,Akram;Poustchi,Hossein;Pak,JamieS;Brennan,Paul;Khademi,Hooman;Genden,EricM;Abnet,ChristianC;Dawsey,SanfordM;Boffetta,Paolo;Malekzadeh,Reza;Sikora,AndrewG
• 通讯作者: Sikora,AndrewG