The immune contexture of colorectal adenomas and serrated polyps

结直肠腺瘤和锯齿状息肉的免疫背景

• 批准号: 9912128
• 负责人: John Anthony Baron
• 金额: $ 11.97万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-09 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912128
• 关键词: Address; Affect; Archives; Benign; CD8B1 gene; Cancer Prognosis; Cell Count; Colorectal; Colorectal Adenoma; Colorectal Cancer; Colorectal Neoplasms; DNA Sequence Alteration; Data; Diabetes Mellitus; Epidemiology; Evolution; Exercise; Formalin; Formulation; Future; Gene Expression; Growth; Image Analysis; Immune; Immune response; Immunofluorescence Immunologic; Immunologic Factors; Individual; Infiltration; Inflammation; Inflammatory; Innate Immune Response; Intervention; Knowledge; Lead; Lesion; Longterm Follow-up; Malignant Neoplasms; Measures; Memory; Methodology; Molecular; Myelogenous; Natural Killer Cells; Neoplasms; Non-Steroidal Anti-Inflammatory Agents; Obesity; PTGS2 gene; Paraffin Embedding; Pathologic; Pathway interactions; Patients; Phenotype; Pilot Projects; Polyps; Preventive Intervention; Recurrence; Regulatory T-Lymphocyte; Resources; Risk; Risk Factors; Slide; Smoking; Specimen; Suppressor-Effector T-Lymphocytes; T cell response; T memory cell; T-Lymphocyte; Technology; Time; Tubular Adenoma; Tumor-infiltrating immune cells; Villous Adenoma; adenoma; cancer invasiveness; carcinogenesis; carcinogenicity; cell type; colon cancer patients; colon carcinogenesis; colorectal cancer prevention; colorectal cancer risk; cytotoxic; cytotoxic CD8 T cells; density; digital imaging; exhaustion; follow-up; immunoreaction; insight; lifestyle factors; macrophage; mortality; nano-string; neoplastic; neutrophil; outcome forecast; prevent; programmed cell death ligand 1; programmed cell death protein 1; protective factors; response; success; tumor; tumor-immune system interactions

The immune reaction to colorectal cancer (CRC) strongly affects its recurrence and mortality. Cancers with high densities of CD8 cytotoxic, Th1, T-regulatory and memory T-cells have a better prognosis than cancers with a Th17, Th2 response. Whether immune factors have a similar impact on early, pre-invasive, carcinogenesis has not been studied. There are 3 common CRC precursor lesions: tubular adenomas (TAs), tubulovillous/villous adenomas (TVs), and sessile serrated polyps (SSPs). These lesions are fairly well characterized molecularly, but little is known regarding the immune reaction to them, even though these occur at a time when carcinogenesis might be more easily countered than after invasive cancer has developed. Preliminary data suggest that as adenomas progress toward invasive cancer, the Th2 and Th17 immune responses increase, and the Th1, CD8+ cytotoxic response diminishes. Unfortunately, these data are derived from relatively small studies, with non-specific methodology. In addition, no study has considered how the immune contexture in any CRC precursor effects the risk of colorectal neoplasia on follow-up, and essentially nothing is known about the immune contexture in SSPs. Moreover, there is a paucity of data regarding the influence of personal and lifestyle factors on the immune responses. To clarify these issues, we propose to utilize the biospecimens and extensive data from three completed studies of colorectal neoplasia, in order to characterize the local immune responses in 500 TAs, 150 TVs, and 150 SSPs, and study associations with future neoplasia. We propose 3 specific aims. 1) To contrast TAs, TVs, and SSPs with regard to infiltration by major T-cell types and immune gene expression 2) To assess the associations of the immune response with precursor lesion progression (size), and 3) To study associations of the immune response in TAs with risk of new neoplastic lesions at follow-up, and evaluate whether any observed association is independent of CRC/precursor risk factors. In exploratory analyses we will also investigate the associations of the immune responses in CRC precursors with risk and protective factors (e.g. obesity or smoking and NSAID use or exercise, respectively). We hypothesize that, as in CRC itself, the Th17 and Th2 responses will have a pro-carcinogenic effect and so will be 1) greater in TVs than in TAs and SSPs, 2) directly associated with polyp size, and 3) independently predictive of risk of recurrent neoplasia. Conversely, we hypothesize that the strength of the Th1, CD8, T-regulatory and memory T cell responses will have the opposite associations. In summary, we will provide the first rigorous and detailed assessment of the immune response to colorectal precursors by studying variability in immune response by precursor type, assessing its impact on lesion growth and recurrence, and identifying epidemiologic correlates of the immune response. This analysis will provide insight into the mechanisms underlying early colorectal carcinogenesis, help identify patients at risk for recurrence, and suggest possible preventive interventions.

对结直肠癌（CRC）的免疫反应强烈影响其复发和死亡率。癌症与 高密度的 CD8 细胞毒性细胞、Th1 细胞、调节性 T 细胞和记忆性 T 细胞比癌症具有更好的预后 具有 Th17、Th2 反应。免疫因素是否对早期、侵袭前、 致癌作用尚未研究。有 3 种常见的 CRC 前驱病变：管状腺瘤 (TA)、 管状绒毛状/绒毛状腺瘤（TV）和无蒂锯齿状息肉（SSP）。这些病变都相当好 分子特征，但对它们的免疫反应知之甚少，即使这些发生 此时癌症发生可能比发生浸润性癌症更容易被抑制。 初步数据表明，随着腺瘤进展为侵袭性癌症，Th2 和 Th17 免疫 反应增加，而 Th1、CD8+ 细胞毒性反应减弱。不幸的是，这些数据是由 来自相对较小的研究，采用非特定的方法。此外，还没有研究考虑过如何 任何 CRC 前体中的免疫环境都会影响随访中结直肠肿瘤的风险，并且本质上 关于 SSP 中的免疫环境我们一无所知。此外，关于该问题的数据也很少 个人和生活方式因素对免疫反应的影响。 为了澄清这些问题，我们建议利用来自三个已完成的生物样本和大量数据 结直肠肿瘤研究，以表征 500 个 TA、150 个 TV 和 150 个 SSP，以及与未来肿瘤的研究关联。我们提出了 3 个具体目标。 1) 对比 TA、TV、 和 SSP 与主要 T 细胞类型的浸润和免疫基因表达有关 2) 评估 免疫反应与前体病变进展（大小）的关联，以及 3) 研究 随访时有新肿瘤病变风险的 TA 的免疫反应，并评估是否存在任何免疫反应 观察到的关联与 CRC/前体危险因素无关。在探索性分析中，我们还将 研究 CRC 前兆的免疫反应与风险和保护因素（例如， 肥胖或吸烟以及非甾体抗炎药的使用或锻炼）。我们假设，正如 CRC 本身一样，Th17 Th2 反应将具有促癌作用，因此 1) TV 中的作用比 TA 和 SSP 中的作用更大， 2) 与息肉大小直接相关，3) 独立预测肿瘤复发的风险。 相反，我们假设 Th1、CD8、T 调节性和记忆性 T 细胞反应的强度将 具有相反的关联。总之，我们将提供第一次严格而详细的评估 通过研究前体类型免疫反应的变异性来研究结直肠前体的免疫反应， 评估其对病变生长和复发的影响，并确定免疫的流行病学相关性 回复。该分析将深入了解早期结直肠癌发生的机制， 帮助识别有复发风险的患者，并建议可能的预防干预措施。