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.

结直肠癌的免疫反应强烈影响其复发和死亡率。的癌症 高密度的CD 8细胞毒性、Th 1、T调节和记忆T细胞比癌症具有更好的预后 Th 17、Th 2反应。免疫因素是否对早期、侵入前、 致癌作用尚未研究。有3种常见的CRC前体病变：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）。这些损伤 其特征在于分子，但很少有人知道对他们的免疫反应，即使这些发生 在癌发生可能比侵袭性癌症发展后更容易被抵抗的时候。 初步数据表明，随着腺瘤向浸润性癌的发展，Th 2和Th 17免疫细胞的免疫功能下降。 应答增加，而Th 1、CD 8+细胞毒性应答减少。不幸的是，这些数据来自 从相对较小的研究，与非特定的方法。此外，没有研究考虑到 任何大肠癌前体的免疫结构都会影响随访时结直肠肿瘤的风险， 对SSP中的免疫结构一无所知。此外，关于这一问题的数据很少。 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，我们建议利用生物标本和广泛的数据，从三个完整的 结直肠肿瘤的研究，以描述500例TA、150例TV和150例TVs中的局部免疫反应。 150例SSP，并研究与未来肿瘤形成的相关性。我们提出三个具体目标。1)对比助教，电视， 和SSP关于主要T细胞类型的浸润和免疫基因表达2）为了评估 免疫应答与前驱病变进展（大小）的相关性，以及3）研究 随访时有新发肿瘤病变风险的TA的免疫应答，并评估是否有任何 观察到的相关性独立于CRC/前体风险因素。在探索性分析中，我们还将 研究CRC前体中免疫应答与风险和保护因素（例如， 肥胖或吸烟和NSAID使用或运动）。我们假设，与CRC本身一样，Th 17 Th 2应答具有促癌作用，因此1）在TV中比在TA和SSP中更大， 2)与息肉大小直接相关，和3）独立预测肿瘤复发的风险。 相反，我们假设Th 1，CD 8，T调节和记忆T细胞反应的强度将 有着相反的联系总之，我们将提供第一个严格和详细的评估， 对结直肠前体的免疫反应通过研究不同前体类型的免疫反应的变异性， 评估其对病变生长和复发的影响，并确定免疫相关的流行病学相关因素。 反应这项分析将提供对早期结直肠癌发生机制的深入了解， 帮助识别有复发风险的患者，并提出可能的预防干预措施。