The immune contexture of colorectal adenomas and serrated polyps

对结直肠癌(CRC)的免疫反应强烈影响其复发和死亡率。患有癌症的人 高密度的CD8细胞毒性、Th1、T调节和记忆T细胞比癌症预后更好 通过Th17、Th2应答。免疫因素是否对早期、侵袭前、 致癌作用尚未被研究过。常见的结直肠癌前驱病变有3种：管状腺瘤(TA)、 管状/绒毛状腺瘤(TV)和无梗锯齿状息肉(SSP)。这些损伤都很好 具有分子特征，但对它们的免疫反应知之甚少，即使发生了这些 在一个癌变可能比浸润性癌症发展之后更容易被对抗的时候。 初步数据表明，随着腺瘤向浸润性癌症发展，Th2和Th17免疫 应答增加，Th1、CD8+细胞毒反应减弱。不幸的是，这些数据是从 来自相对较小的研究，使用非特定的方法。此外，还没有研究考虑到 任何结直肠癌前体中的免疫环境都会影响随访的结直肠肿瘤的风险，而且本质上 对SSP中的免疫环境一无所知。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。 为了阐明这些问题，我们建议利用生物标本和来自三个已完成的 结直肠肿瘤的研究，以表征500个TA、150个TV和 150个SSP，并研究与未来肿瘤的相关性。我们提出了三个具体目标。1)对比助教、电视、 和SSP关于主要T细胞类型和免疫基因表达的渗透2)以评估 免疫反应与前驱病变进展(大小)的相关性，以及3)研究 有新的肿瘤病变风险的TAS患者随访时的免疫反应，并评估是否有 观察到的相关性与结直肠癌/先兆风险因素无关。在探索性分析中，我们还将 研究结直肠癌先兆的免疫反应与风险和保护因素的关系(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，就像在CRC本身一样，Th17 并且Th2应答将具有促癌作用，因此在电视中将比在TA和SSP中更大， 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调节和记忆T细胞反应的强度将 有相反的联想。总括而言，我们将提供首份严格而详细的 通过研究不同前体类型免疫反应的变异性来研究对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 回应。这一分析将为早期结直肠癌发生的机制提供洞察力。 帮助识别有复发风险的患者，并提出可能的预防措施。

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.