Characterization of immune escape mechanisms associated with tumor progression and resistance to chemotherapy

与肿瘤进展和化疗耐药相关的免疫逃逸机制的表征

• 批准号: 446146972
• 负责人: Professorin Dr. Barbara Seliger
• 金额: --
• 依托单位: Centre de Recherche des Cordeliers - UMRS 1138
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/446146972?language=en
• 关键词: Characterization; immune; escape; mechanisms; associated

Cancer is one of the most prominent public health challenges, and colorectal cancer (CRC) is the third most common cancer in men and the second in women worldwide. Although recent developments in cancer therapy have a significant clinical impact, only a subset of patients exhibit long-term clinical responses and the rationale selection of treatment for CRC patients should be improved. Therefore, a better understanding of the molecular and cellular immune escape mechanisms leading to tumor progression and resistance to therapy is necessary. It is known that the tumor microenvironment (TME), and in particular the Immunoscore, has a profound impact on tumor development and on response to chemotherapy. Host-derived factors can also mediate immune escape mechanisms. Indeed, there exists increasing evidence that tumor-intrinsic signaling and immune modulatory molecules play a key role in regulating the immune suppressive TME and immune escape.We here propose to perform an in-depth analysis of the colorectal tumor landscape to (1) decipher the immune mechanisms associated with response to chemotherapy in CRC patients and (2) unravel the mechanisms underlying the immune control of cancer progression, spanning from stage II to the metastatic stage IV. We will study the immune landscape of the TME as well as the genomics, immunomics and miRNA alterations in the tumor cells by exploiting access to large collections of human samples and using state-of-the-art technologies. The role of immune modulatory molecules, such as HLA class I APM components, HLA-G and PD-L1, will also be explored. On one hand, by comparing CRC patients treated or not with chemotherapy, we expect to reveal intrinsic and/or extrinsic escape mechanisms in non-responding patients. On the other hand, by assessing the tumor immune landscape in CRC patients from stage II to IV, we expect to identify mechanisms of cancer progression and of cancer recurrence, especially at the metastatic stage. The data obtained will then be correlated with the Immunoscore classification of CRC patients in order to understand the mechanisms associated with high and low Immunoscore at all stages of this disease as well as factor(s) associated with response to chemotherapy.This analysis should allow to identify prognostic and predictive biomarkers, which not only will have an impact on the understanding of immune escape mechanisms, but also on cancer classification, and on the development of therapies for better patient clinical management.

癌症是最突出的公共卫生挑战之一，结直肠癌（CRC）是全球男性第三大常见癌症，女性第二大常见癌症。尽管癌症治疗的最新进展具有显著的临床影响，但只有一部分患者表现出长期临床应答，因此应改进CRC患者治疗的合理选择。因此，更好地了解导致肿瘤进展和治疗抵抗的分子和细胞免疫逃逸机制是必要的。众所周知，肿瘤微环境（TME），特别是免疫评分，对肿瘤的发展和对化疗的反应有着深远的影响。宿主衍生因子也可以介导免疫逃逸机制。事实上，越来越多的证据表明，肿瘤内在信号和免疫调节分子在调节免疫抑制性TME和免疫逃逸中起着关键作用。我们在这里建议对结直肠肿瘤景观进行深入分析，以（1）破译CRC患者对化疗反应相关的免疫机制，（2）解开免疫控制癌症进展的潜在机制，从II期到转移性IV期。我们将研究TME的免疫景观以及肿瘤细胞中的基因组学，免疫组学和miRNA改变，通过利用大量的人类样本和使用最先进的技术。免疫调节分子的作用，如HLA I类APM成分，HLA-G和PD-L1，也将被探讨。一方面，通过比较接受或未接受化疗的结直肠癌患者，我们期望揭示无应答患者的内在和/或外在逃避机制。另一方面，通过评估II期至IV期CRC患者的肿瘤免疫状况，我们期望确定癌症进展和癌症复发的机制，特别是在转移阶段。然后将获得的数据与CRC患者的免疫评分分类相关联，以了解在该疾病的所有阶段与高和低免疫评分相关的机制以及与对化疗的反应相关的因素。该分析应允许鉴定预后和预测生物标志物，这不仅将对免疫逃逸机制的理解产生影响，而且对癌症分类和对更好的患者临床管理的疗法的开发也有影响。