Co-Evolution Mechanisms of Pre-Cancer-Immune Interactions in Shaping Adaptive Cytotoxicity and Myeloid-Derived Suppression

形成适应性细胞毒性和骨髓源性抑制的癌前免疫相互作用的共同进化机制

• 批准号: 10518849
• 负责人: Ken S Lau
• 金额: $ 41.77万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10518849
• 关键词: Algorithms; Atlases; Big Bang Cosmology; Biological Assay; Biological Models; CRISPR/Cas technology; Cancer Biology; Cell Communication; Cells; Clinical; Coculture Techniques; Colorectal Cancer; Communication; Complex; Computer Models; Cytotoxic T-Lymphocytes; DNA sequencing; Data; Development; Dysplasia; Ecosystem; Elements; Environment; Epithelial; Event; Evolution; Exhibits; Genetic; Genomics; Human; Hyperactivity; Immune; Immune system; Immunosuppression; Immunotherapy; In Vitro; Individual; Intervention; Knowledge; Light; Malignant - descriptor; Malignant Neoplasms; Maps; Metaplasia; Modeling; Molecular; Monitor; Morphology; Mutation; Myelogenous; Neighborhoods; Organoids; Pathologic; Pathologist; Pathway interactions; Patients; Phylogeny; Polyps; Prevention; Sampling; Shapes; Somatic Mutation; Specimen; System; Systems Analysis; T cell clonality; Technology; Testing; Therapeutic Intervention; Tumor stage; Tumor-infiltrating immune cells; Work; adaptive immunity; arms race; cell community; colon tumorigenesis; cytotoxic; cytotoxicity; exome sequencing; genetic evolution; immunogenic; laser capture microdissection; microbiota; multiple omics; multiplexed imaging; neoantigens; neoplastic cell; new technology; patient prognosis; patient response; predictive modeling; premalignant; pressure; reconstruction; response; scaffold; single cell sequencing; single-cell RNA sequencing; stem; stem cells; stemness; transcriptomics; transfer learning; tumor; tumor heterogeneity; tumor progression; tumor-immune system interactions; tumorigenesis

PROJECT SUMMARY/ABSTRACT Project 3: Co-Evolution Mechanisms of Pre-Cancer-Immune Interactions in Shaping Adaptive Cytotoxicity and Myeloid-Derived Suppression The pre-cancer-to-cancer transition is a critical juncture in colorectal cancer (CRC) biology that has clinical value in prevention and surveillance. This transition is characterized by an “evolutionary arms race” where the body’s immune system seeks to eliminate the tumor while the tumor cells evolve mechanisms to suppress and evade the immune system. The small number of human pre-precancers that transition into cancer precludes effective predictive modeling of critical genetic and microenvironmental factors that drive these alterations. Herein, we will leverage regional intratumoral heterogeneity, due to asynchronicity of evolution, with spatially resolved profiling technologies on human tumor specimens to build trajectories of pre-cancer transition into malignancy. We will model two pathways of pre-cancer transitions, the conventional pathway driven by mutations in the WNT pathway and the serrated pathway characterized by an immunogenic microenvironment. Our previous pre- cancer atlas describes a dichotomy between stemness in tumor cells and cytotoxic T cells in the microenvironment between these two pathways. Thus, we hypothesize that pre-cancers gain stemness to enable epithelial mechanisms to suppress a cytotoxic immune environment, resulting in malignant evolution. In Aim 1, we will use spatially resolved DNA sequencing to map genetic evolution of pre-cancer cells with selective pressures conferred by neoantigen-specific adaptive immunity. In Aim 2, we will use integrative spatial multi- omics to interrogate tumor mechanisms to modulate immune cell communication networks during progression. By combining novel technologies with data-driven systems modeling, we will shed light on the complex interplay between human tumors and their microenvironment that shape their transition trajectories into malignancy.

项目总结/摘要 项目3：癌症前免疫相互作用的协同进化机制 细胞毒性和髓源性抑制 癌前到癌的转变是结直肠癌（CRC）生物学中具有临床价值的关键时刻 在预防和监测方面。这种转变的特点是“进化的军备竞赛”， 免疫系统寻求消除肿瘤，而肿瘤细胞进化出抑制和逃避的机制。 免疫系统.少量的人类前期癌转变为癌症排除了有效的 对驱动这些改变的关键遗传和微环境因素进行预测建模。在此，我们将 利用空间分辨分析，利用区域性肿瘤内异质性（由于演变的连续性） 在人类肿瘤标本上使用技术，以建立癌前病变向恶性肿瘤转变的轨迹。我们将 建立两种癌前转变途径的模型，传统途径由WNT突变驱动， 途径和特征在于免疫原性微环境的锯齿状途径。我们之前的预- 癌症图谱描述了肿瘤细胞中的干细胞和肿瘤细胞中的细胞毒性T细胞之间的二分法。 这两种途径之间的微环境。因此，我们假设癌前病变获得了干性， 上皮机制抑制细胞毒性免疫环境，导致恶性演变。在目标1中， 我们将使用空间分辨DNA测序来绘制癌前细胞的遗传进化， 新抗原特异性适应性免疫所带来的压力。在目标2中，我们将使用综合空间多- 组学研究肿瘤机制，以调节进展过程中的免疫细胞通讯网络。 通过将新技术与数据驱动的系统建模相结合，我们将揭示复杂的相互作用 人类肿瘤和它们的微环境之间的联系，这些微环境塑造了它们向恶性肿瘤转变的轨迹。