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

癌症是最突出的公共卫生挑战之一，结直肠癌(CRC)是世界上第三大常见男性癌症和第二大女性癌症。尽管癌症治疗的最新进展对临床产生了显著的影响，但只有少数患者表现出长期的临床反应，结直肠癌患者选择治疗的合理性应该得到改善。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)，尤其是免疫核心，对肿瘤的发展和化疗的反应有着深远的影响。宿主来源的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，肿瘤固有的信号和免疫调节分子在调节免疫抑制的TME和免疫逃逸方面发挥了关键作用。我们在此提议对结直肠癌进行深入的分析，以(1)破译与结直肠癌患者化疗反应相关的免疫机制，(2)揭示从II期到转移IV期的癌症进展的免疫控制机制。我们将利用获取大量人类样本和使用最先进的技术来研究TME的免疫环境以及肿瘤细胞中的基因组学、免疫学和miRNA变化。还将探讨免疫调节分子的作用，如人类白细胞抗原I类APM成分、人类白细胞抗原G和PD-L1。一方面，通过比较接受化疗或未接受化疗的结直肠癌患者，我们期望揭示无反应患者的内在和/或外在逃逸机制。另一方面，通过评估II-IV期结直肠癌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结直肠癌患者的免疫评分分类相关联，以了解该病所有阶段免疫评分高和低的相关机制以及与化疗反应相关的因素(S)。这种分析应该能够识别预后和预测生物标记物，这不仅将对免疫逃逸机制的理解产生影响，而且对癌症分类和更好地对患者临床管理的治疗方法的发展产生影响。

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.