(PQC3) Using an Immunoscore to Assess Tumor-medicated Immune Variations in African -American

描述（由申请方提供）：尽管有大量证据证明肿瘤介导的免疫应答对前列腺癌患者结局的重要性，但尚无研究充分评价非裔美国人患者中的肿瘤介导的免疫应答。考虑到非裔美国人种族是更具侵袭性和致命性的前列腺癌的风险因素，本研究的目的是检验总体假设，即肿瘤浸润淋巴细胞进入前列腺的数量和定位差异与前列腺癌种族健康差异有关，雄激素信号调节这一过程。 在这项研究中，我们将利用2003年至2013年期间收集的前列腺组织生物储存库，其中包含超过6，500份档案前列腺癌标本，其中25%（1，630）来自非洲裔美国男性。为了以明确的方式检验我们的假设，我们将利用“免疫评分”的概念。“免疫评分是一种基于肿瘤中CD 3+和CD 8 + T淋巴细胞定量的综合评分，已经被发现是结直肠癌患者的一个强有力的预测指标，并且只是开始探索其他实体瘤类型。在 我们的具体目标1，我们将调整现有的免疫评分方法，使其与前列腺癌兼容并适用于前列腺癌，并将在来自我们组织库的非洲裔美国人和高加索人患者的小的初步小组中测试计算前列腺癌免疫评分的再现性和稳健性。在我们的特定目标2中，我们将确定非裔美国人（1，630）和白人（1，630）患者的大型队列中的前列腺癌免疫评分和雄激素受体状态，我们也有10年的随访数据。然后，我们将能够确定非洲裔美国人和高加索人之间是否存在差异：前列腺癌免疫评分，肿瘤浸润T淋巴细胞（CD 3+，CD 4+和CD 8+）的谱/数量，和/或雄激素受体状态;以及种族是否可以预测这些变量中的任何一个。在我们的特定目标3中，我们将进行考克斯回归分析和统计建模，以确定前列腺癌免疫评分和/或AR状态是否是非裔美国人和/或高加索局限性前列腺癌患者长期临床结局（生化复发和/或疾病特异性死亡率）的预测因子。如果是这样的话，我们将能够构建一个基于免疫学的分类器，临床医生可以使用它来更好地预测非洲裔美国前列腺癌患者的结果，这是目前不存在的，也是迫切需要的。这项工作也将为未来围绕种族，肿瘤浸润T淋巴细胞和前列腺癌雄激素信号传导的机制研究提供临床依据。

DESCRIPTION (provided by applicant): Despite a body of evidence demonstrating the importance of the tumor-mediated immune response to the outcome of prostate cancer patients, no studies have adequately evaluated the tumor-mediated immune response in African American patients. Given that the African American race is a risk factor for more aggressive and lethal prostate cancer, the purpose of this study is to test the overall hypothesis that difference in the quantity and localization of tumor-infiltrating lymphocytes into the prostate gland correlat with PCa racial health disparities and that androgen signaling regulates this process. For this study, we will utilize a prostate tissue biorepository collected between 2003 and 2013, containing over 6,500 archival prostate cancer specimens, 25% (1,630) of which are from African American men. To test our hypothesis in a definitive way, we will utilize the concept of an "immunoscore." The immunoscore, a combined score based on the quantitation of CD3+ and CD8+ T lymphocytes in a tumor, has already been found to be a strong predictive indicator in patients with colorectal cancer and is only starting to be explored for other solid tumor types. In our Specific Aim 1, we will adapt existing immunoscoring methodology to be compatible with and applicable to prostate cancer, and will test the reproducibility and robustness of calculating the prostate cancer immunoscore in a small, preliminary panel of African American and Caucasian patients from our tissue bank. In our Specific Aim 2, we will determine the prostate cancer immunoscore and androgen receptor status in a large cohort of African American (1,630) and Caucasian (1,630) patients, for which we also have 10-year follow-up data. We will then be able to determine if differences exist between African Americans and Caucasians with respect to: prostate cancer immunoscores, the spectrum/quantity of tumor-infiltrating T lymphocytes (CD3+, CD4+, and CD8+), and/or androgen receptor status; and if race is predictive of any of these variables. In our Specific Aim 3, we will perform Cox regression analysis and statistical modeling to determine if the prostate cancer immunoscore and/or AR status are predictors of long-term clinical outcomes (biochemical recurrence and/or disease-specific mortality) in African American and/or Caucasian patients with localized prostate cancer. If so, we will be able to construct an immunoscore-based classifier that clinicians can use to better predict outcome in their African American patients with prostate cancer-something that currently doesn't exist and is desperately needed. This work will also provide the clinical justification for future mechanisti studies surrounding race, tumor-infiltrating T lymphocytes, and androgen signaling in prostate cancer.