Tumor induced senescent and suppressor T cells - a novel mechanism of immune evas

描述(申请人提供)：头颈部鳞状细胞癌(SCCHN)仍然是美国最致命的癌症之一。尽管出现了许多新的治疗方法，但在改善这种疾病的发病率或死亡率方面几乎没有成功。免疫学的不断进步使免疫治疗成为当前和未来癌症研究的活跃领域。然而，设计SCCHN的免疫治疗策略需要了解肿瘤的微环境。我们最近观察到，肿瘤微环境中T淋巴细胞的功能障碍与一个类似衰老的过程有关。此外，这些细胞不仅具有衰老特征，而且还具有与抑制细胞一致的功能变化。未来癌症患者免疫治疗方法的成功取决于保护T细胞免受肿瘤部位这种变化的影响，并提高其效率。MCL-1是一个幸存的Bcl2家族成员，最近被证明是成熟T淋巴细胞生存所必需的。我们的初步结果表明，Mcl-1可能在保护T淋巴细胞免受肿瘤诱导的衰老中发挥关键调节作用，这是通过促衰老和抗凋亡分子P53介导的。值得注意的是，在支持生存的Bcl-2家族成员中，Mcl-1是在免疫治疗中使用的细胞因子如IL-2、IL-7和IL-12作用下显著上调表达的主要蛋白质。目前的应用将试图阐明Mcl-1在肿瘤微环境中保护SCCHN相关淋巴细胞免于衰老的作用和功能机制。基本的科学方法将使用肿瘤诱导T细胞衰老的模型来进一步描述这一过程中涉及的机制，重点是Mcl-1对P53衰老活性的调节。将对这些衰老T细胞的抑制功能进行进一步的表征，以更好地了解这一过程对免疫系统的影响。该提案的翻译部分将评估新发现的衰老抑制T细胞的诊断潜力，并阐明细胞内靶点，以改进目前SCCHN的免疫治疗方案。公共卫生相关性：项目描述当前项目的目标是阐明一种新形式的肿瘤免疫逃避。通过更好地了解癌症相关功能障碍T细胞形成的分子机制，可以设计出新的诊断和治疗方案。该提案的核心是解释癌症是如何通过直接改变T细胞来部分逃避免疫系统的，目的是提高新兴的基于免疫的治疗的成功。

DESCRIPTION (provided by applicant): Squamous cell carcinoma of the head and neck (SCCHN) remains one of the deadliest cancers in the United States. Despite many emerging new treatments there has been almost no success in improving either the morbidity or mortality of this disease. Continuing advances in immunology make immunotherapy an active area for current and future cancer research. However, the design of immunotherapeutic strategies for SCCHN requires an understanding of the tumor microenvironment. We have recently observed that a senescence-like process is involved in the dysfunction of T lymphocytes in the tumor microenvironment. Further, these cells not only have senescent features, but in addition have functional changes consistent with suppressor cells. Future success of immunotherapeutic approaches for cancer patients are dependent on the protection of T cells from such changes at the tumor site and the enhancement of their efficiency. Mcl-1, a prosurvival Bcl-2 family member, has recently been demonstrated to be required for the survival of mature T lymphocytes. Our preliminary results suggest that Mcl-1 may have a key regulatory role in the protection of T lymphocytes from tumor-induced senescence that is mediated through the pro-senescent and -apoptotic molecule, p53. Noteworthy, among the pro-survival Bcl-2 family members, Mcl-1 is the major protein to undergo significant upregulated expression in response to cytokines used for immunotherapy, such as, IL-2, IL-7, and IL-12. The current application will attempt to elucidate the role and functional mechanisms of Mcl-1 in the protection of SCCHN-associated lymphocytes from senescence at the tumor microenvironment. The underlying scientific approach will employ a model of tumor-induced senescence of T cells to further characterize the mechanisms involved in this process with an emphasis on the regulation of p53 senescent activity by Mcl-1. Further characterization of the suppressor function of these senescent T cells will be performed to better understand the impact of this process on the immune system. The translational components of this proposal will evaluate the diagnostic potential of the newly identified senescent suppressor T cells and elucidate intracellular targets for the improvement of current immunotherapeutic protocols for SCCHN. PUBLIC HEALTH RELEVANCE: Project Narrative The goal of the current project is to elucidate a new form of tumor immune evasion. By gaining a better understanding of the molecular mechanisms involved in the formation of cancer associated dysfunctional T cells new diagnostic and therapeutic regimens can be devised. The proposal centers on explaining how cancer in part evades the immune system through directly altering T cells with the goal of improving the success of emerging immune based therapies.