Mechanisms of immune control of intratumor heterogeneity and clonal competition

肿瘤内异质性和克隆竞争的免疫控制机制

• 批准号: 10552000
• 负责人: Flaminia Talos
• 金额: $ 17.65万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10552000
• 关键词: Address; Automobile Driving; Biological Assay; Cells; Chemotaxis; Clinical; Clonal Evolution; Clonal Expansion; Color; Communities; Complex; Coupled; Disease; Disease Outcome; Disease Resistance; Drug resistance; Ecology; Ecosystem; Enabling Factors; Equilibrium; Evolution; Exhibits; Exploratory/Developmental Grant; Future; Genetic Determinism; Genomics; Geography; Goals; Growth; Human; Immune; Immune system; In Vitro; Interferon Type II; Intervention; MHC Class II Genes; Malignant Neoplasms; Malignant neoplasm of prostate; Maps; Minor; Modeling; Molecular; Molecular Profiling; Mutation; Organoids; Outcome; Phenotype; Population; Role; Shapes; Solid; Source; T cell infiltration; Time; Treatment Failure; advanced disease; anticancer research; cancer therapy; chemokine; design; fitness; immunogenic; immunological intervention; immunoregulation; improved; in vivo; innovation; insight; member; mouse model; multiple omics; new therapeutic target; non-genetic; novel; pre-clinical; prevent; prostate cancer model; transcriptomics; translational approach; treatment strategy; tumor; tumor heterogeneity; tumor microenvironment; tumor-immune system interactions

PROJECT SUMMARY/ABSTRACT Intratumor heterogeneity (ITH) and clonal evolution pose tremendous challenges in designing effective and durable cancer therapies. This is highly relevant for PCa, a prime example of a highly heterogenous disease where fluctuating cellular subpopulations (“clones”) with distinct mutational and phenotypic profiles can coexist and evolve independently, diversify and compete during the course of the disease. The majority of ITH studies centers on genetic determinants, while non-genetic variability such as due to spatial clonal distributions and interactions of tumor subpopulations with each other and with the immune TME remain poorly understood. These mechanisms are multifaceted, context-dependent and difficult to investigate experimentally in vivo. However, these complex interactions might hold powerful anti-tumor interventions. For instance, mechanisms of elimination of “loser” cells/clones could be exploited to lower overall tumor fitness and new targeted therapies could be developed to counteract the factors that enable clonal dominance. We recently generated new reductionist models of ITH that reflect, at least in part, the clonal fitness diversity of human PCa. By incorporating multicolor lineage tracing in mouse models, longitudinal organoid studies and single cell transcriptomics, we showed that less severe models accommodate the coexistence of multiple growing tumor subpopulations. In contrast, aggressive tumors exhibit a drastic and rapid clonal reduction, emergence of larger dominant populations as slower-growing populations are out-competed by fast-growing ones in vivo and in vitro, and massive TME remodeling. In the same time, some minor populations persist and might serve as a reservoir for drug-resistant clones. Moreover, the minor populations have distinct immunoediting molecular signatures marked by increased expression of Cxcl9/Cxcl11 and MHC class II members. We hypothesize that direct competition mechanisms between dominant and minor clones within specialized TME niches coupled with fitness effects of the immune system on clonal expansions determine the ITH in PCa. The goal of this proposal is to identify molecular mechanisms and cellular contexts underlying clonal interactions with each other and with TME by pursuing 1) Functional mapping of tumor competitive landscapes in mouse models of PCa by spatial transcriptomic analyses and 2) Elucidate the role of Cxcl9/11 in reducing the fitness potential of minor clones by novel competition-chemotaxis and T-cell infiltration organoid assays and in vivo immunomodulatory interventions. Results from these studies will not only greatly expand our understanding of population-level interactions in tumors, but also uncover new targetable immunoediting mechanisms that operate at clonal level in driving clonal diversification and selection with impact on preventing progression to advanced disease and drug resistance.

项目总结/摘要 肿瘤内异质性（ITH）和克隆进化对设计有效的肿瘤治疗方案提出了巨大的挑战。 和持久的癌症治疗。这与前列腺癌高度相关，前列腺癌是高度异质性疾病的一个主要例子 其中具有不同突变和表型特征的波动细胞亚群（“克隆”）可以共存 并且在疾病过程中独立进化、多样化和竞争。大多数ITH研究 中心的遗传决定因素，而非遗传变异，如由于空间克隆分布， 肿瘤亚群之间以及与免疫TME之间的相互作用仍然知之甚少。这些 其机制是多方面的，依赖于环境，难以在体内进行实验研究。然而，在这方面， 这些复杂的相互作用可能具有强大的抗肿瘤干预作用。例如，消除机制 “失败者”细胞/克隆可以用来降低肿瘤的整体适应性，新的靶向治疗可以被用来治疗肿瘤。 来抵消克隆优势的因素。我们最近产生了新的简化论者 ITH的模型，反映，至少部分，克隆适合度多样性的人PCa。通过将 在小鼠模型、纵向类器官研究和单细胞转录组学中的谱系追踪，我们表明， 不太严重的模型适应多种生长肿瘤亚群的共存。与此相反， 侵袭性肿瘤表现出急剧和快速的克隆减少，出现更大的优势种群， 生长缓慢的种群在体内和体外都被快速生长的种群所淘汰， 重塑与此同时，一些少数群体持续存在，可能成为耐药菌株的储存库。 克隆此外，少数群体具有不同的免疫编辑分子特征，其标记为增加的免疫编辑分子。 Cxcl 9/Cxcl 11和MHC II类成员的表达。我们假设直接竞争机制 在专门的TME生态位内的显性和次要克隆之间， 克隆扩增系统决定PCa中的ITH。这项提案的目标是确定分子 机制和细胞背景下的克隆相互作用和与TME通过追求1） PCa小鼠模型中肿瘤竞争景观的空间转录组学功能定位 分析和2）阐明Cxcl 9/11在通过新的Cxcl 9/11基因降低次要克隆的适应性潜力中的作用。 竞争趋化性和T细胞浸润类器官测定和体内免疫调节干预。 这些研究的结果不仅将大大扩展我们对种群水平相互作用的理解， 而且还揭示了新的靶向免疫编辑机制，这些机制在克隆水平上起作用， 克隆多样化和选择对预防进展为晚期疾病和药物有影响 阻力