Mechanisms of Immune Evasion by Ocular Tumors

眼部肿瘤的免疫逃避机制

• 批准号: 7892439
• 负责人: KYLE C MCKENNA
• 金额: $ 37.5万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7892439
• 关键词: Adoptive Transfer; Affect; Animal Model; Antibodies; Attenuated; B-Lymphocytes; Biological Assay; CD8B1 gene; Cell surface; Cells; Chickens; Congenic Mice; Development; Dichloromethylene Diphosphonate; Effector Cell; Eye; Eye Neoplasms; Failure; ITGAM gene; Immune; Immune response; Immunosuppression; Immunosuppressive Agents; Immunotherapy; In Vitro; Infiltration; Lead; Life; Liposomes; Lymphocyte Function; Measures; Mediating; Mus; Myelogenous; Myeloid Cells; NG-Nitroarginine Methyl Ester; NOS2A gene; Neoplasm Metastasis; Nitric Oxide; Nitric Oxide Synthase; Ovalbumin; Patients; Population; Production; Publications; Resistance; Skin; Skin Neoplasms; Staining method; Stains; T-Lymphocyte; Testing; Tumor Antigens; Uveal Melanoma; Wild Type Mouse; anterior chamber; apoptosis in lymphocytes; base; cellular imaging; collagenase; granzyme B; in vivo; inhibitor/antagonist; macrophage; melanoma; novel; outcome forecast; prevent; public health relevance; response; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Melanomas develop within the eye despite the induction of melanoma-specific CD8+ cytolytic T lymphocyte (CTL) responses which indicates that these tumors somehow evade tumoricidal CTL. Uveal melanomas that are infiltrated by myeloid cells are associated with a poor patient prognosis and we were first to demonstrate in an animal model that the failure to control tumor growth in the anterior chamber of the eye correlates with the accumulation of CD11b+ myeloid cells which inhibit CTL responses in vitro via nitric oxide (NO) production. Accordingly, we hypothesize that myeloid cells promote ocular tumor growth by inhibiting CTL responses within the tumor microenvironment. We demonstrate in preliminary studies the novel observation that GR-1+ F4/80 negative CD11b+ cells accumulate within ocular tumors which are resistant to CTL responses, whereas the same tumors developing within the skin which are sensitive to CTL are infiltrated by GR-1 negative/ F4/80+ CD11b+ cells. Hence, immune suppressive mechanisms which maintain "immune privilege" within the eye by attenuating innate and adaptive immune responses may condition ocular tumor associated CD11b+ cells toward an immunosuppressive and not tumoricidal type as well as directly inhibit CTL responses. Our Specific Aims will test three related alternative hypotheses about the mechanisms that inhibit CTL responses within the ocular tumor microenvironment. In Aim #1 we will directly determine the influence of tumor associated CD11b+ cell subsets on the tumoricidal activity of CTL effectors by selectively eliminating GR-1+ cells , F4/80+ cells or both cell populations in mice with established eye or skin tumors prior to adoptive transfer of tumor-specific CTL. In Aim #2 we will determine the influence of NO production on the tumoricidal activity of CTL by transferring tumor-specific CTL into tumor bearing mice that are deficient in NO production. We will also directly evaluate NO mediated immunosuppressive and tumoricidal activity of CD11b+ cell subsets isolated from skin and eye tumors to determine whether inhibited tumoricidal activity by CD11b+ cells within the eye contributes to ocular tumor progression. In Aim #3 we will determine the influence of ocular expression of immune suppressive molecules (FasL, PD-1L, Trail, and TGF-¿) on the tumoricidal activity of CTL by transferring tumor-specific CTL into mice deficient in these molecules before tumor challenge. PUBLIC HEALTH RELEVANCE: Uveal melanomas infiltrated by myeloid cells are associated with a poor patient prognosis. This application will determine the influence of myeloid cells on suppression of tumoricidal immune responses in an ocular tumor microenvironment. Understanding the contribution of myeloid cells to immune suppression and tumor growth may lead to the development of immunotherapies that promote tumor elimination in the eye and prevent metastasis.

描述（由适用提供）：尽管诱导了黑色素瘤特异性CD8+细胞溶解T淋巴细胞（CTL）反应，但黑色素瘤仍在眼睛内发展，这表明这些肿瘤以某种方式逃避了结核病CTL。由髓样细胞浸润的紫抗体黑色素瘤与较差的患者提示有关，我们首先在动物模型中证明，眼睛前腔的肿瘤生长未能与CD11b+髓样细胞的积累相关，这些CD11b+髓样细胞的积累，该细胞通过一氧化氧化物（NO）（NO）抑制了体内CTL反应。根据，我们假设髓样细胞通过抑制肿瘤微环境中的CTL反应来促进眼部肿瘤的生长。我们在初步研究中证明了新的观察结果表明，GR-1+ F4/80阴性CD11b+细胞积累在眼部肿瘤中，对CTL反应具有抗性，而在皮肤中发育中的同一肿瘤对CTL敏感，GR-1阴性/F4/80+ CD11b+细胞渗透了CTL。因此，通过衰减先天和适应性免疫调查的免疫抑制机制，可以在眼睛内保持“免疫特权”，这可能调节眼部肿瘤相关的CD11b+细胞对免疫抑制和非肿瘤类型，而不是直接抑制CTL反应。我们的具体目的将测试有关抑制眼部肿瘤微环境中CTL反应的机制的三个相关替代假设。在AIM＃1中，我们将直接确定与肿瘤相关的CD11b+细胞亚群对CTL效应的结节活性的影响，通过选择性地消除具有既定的眼睛或皮肤肿瘤的小鼠中的GR-1+细胞，F4/80+细胞或两个细胞群，或者在肿瘤特异性CTL的养育中。在AIM＃2中，我们将通过将肿瘤特异性CTL转移到无生产中确定性的肿瘤轴承小鼠中来确定NO生产对块茎特异性CTL的影响。我们还将直接评估没有从皮肤和眼肿瘤中分离出的CD11b+细胞子群的介导的免疫抑制和块茎活性，以确定眼睛内CD11b+细胞抑制块茎活性是否有助于眼肿瘤的进展。在AIM＃3中，我们将通过将肿瘤特异性CTL转移到肿瘤挑战前的这些分子中，通过将肿瘤特异性CTL转移到特定的小鼠中，来确定免疫抑制分子（FASL，PD-1L，TRAIL和TGF- - ）的眼部表达对CTL的结核性活性的影响。公共卫生相关性：髓样细胞浸润的紫veal黑色素瘤与患者提示不佳有关。该应用将确定髓样细胞对眼部肿瘤微环境中结成核免疫抑制的影响。了解髓样细胞对免疫抑制和肿瘤生长的贡献可能会导致免疫疗法的发展，从而促进眼睛中消除肿瘤并预防转移。