Deciphering the role of tumor-macrophage crosstalk during metastatic dissemination to the peritoneum

项目摘要/摘要： 在过去的十年中，检查点封锁免疫疗法极大地提高了患者的总体存活率 晚期黑色素瘤患者。然而，这些疗法未能治疗许多其他类型的癌症，包括 胰腺癌、肝癌和胃癌。了解成功的肿瘤保护性免疫反应 从长远来看，癌症幸存者可以促进对抗肿瘤免疫反应和 开发新的治疗策略。发生皮肤免疫相关不良反应的黑色素瘤患者 包括皮疹和白癜风在内的事件(IrAEs)的总体存活率比那些未受影响的患者更好。然而， 将皮肤irAEs与特殊的抗肿瘤免疫联系起来的免疫机制尚不清楚。因此， 具体目标1将全面表征表型、持久性、抗原特异性和定位。 使用单细胞RNA-SEQ对白癜风和皮疹影响的黑色素瘤幸存者的抗肿瘤T细胞反应进行研究， 单细胞TCR-seq、批量TCR-seq和10倍空间转录。我假设，与未受影响的人相比 黑色素瘤患者，真皮IRAE患者维持更持久的促炎T细胞反应 聚焦于肿瘤的TCR曲目。该项目将在诺里斯-科顿癌症中心(NCCC)进行， 由包括内科肿瘤学家、外科医生、皮肤科医生和免疫学家在内的协作团队提供支持。这个 赞助商的实验室拥有肿瘤免疫学、记忆T细胞和翻译研究方面的专业知识，赞助商 有丰富的研究生辅导经验。培训的重点将是知识和新奇 掌握10倍空间转录等技术技能，顺利完成课题研究。此外, 培养过渡到K00阶段的专业人员也是一项重要的培训目标。转型 到K00期，研究的重点将是肿瘤免疫治疗的耐药机制和 利用微生物组开发新的免疫治疗策略。肿瘤内微生物区系 最近发现，即使在免疫感冒的癌症类型中，也能成功地促进肿瘤免疫，但确切的分子 细胞机制仍不清楚。我推测某些微生物群可以重新编程免疫 细胞和肿瘤细胞本身，导致更多的促炎抗肿瘤微环境。这个 研究将在一个杰出的癌症免疫学实验室进行，该实验室在两个翻译领域都处于领先地位 临床前模型中的人体研究和机制基础研究。研究性培训将是 重点使用小鼠模型、基因组学、表观基因组学、代谢组学和细胞免疫学方法 以确定克服免疫治疗耐药肿瘤生长的关键机制。到年底的目标 F99/K00训练是为了了解肿瘤保护性免疫反应的特点和最佳设计 新的癌症免疫疗法。这些培训将为最终的职业生涯提供关键的知识和技能 目的在学术界建立一个研究小组，致力于开发成功的免疫治疗方案。

Project Summary/Abstract: In the past decade, checkpoint blockade immunotherapies have greatly improved the overall survival of advanced melanoma patients. However, these therapies have failed to treat many other cancer types, including cancers of the pancreas, liver, and stomach. Understanding the successful tumor protective immune responses in long term cancer survivors could promote the understanding of anti-tumor immune responses and the development of novel therapeutic strategies. Melanoma patients who developed dermal immune-related adverse events (irAEs), including rash and vitiligo, have better overall survival than those unaffected patients. However, the immune mechanisms linking dermal irAEs with exceptional anti-tumor immunity remain unknown. Thus, specific aim 1 will comprehensively characterize the phenotype, persistence, antigen specificity, and localization of anti-tumoral T cell responses in both vitiligo and rash affected melanoma survivors using single-cell RNA-seq, single-cell TCR-seq, bulk TCR-seq and 10X spatial transcriptomics. I hypothesize that compared to unaffected melanoma patients, dermal irAE patients maintain more durable proinflammatory T cell responses with a more tumor-focused TCR repertoire. This project will be conducted at the Norris-Cotton Cancer Center (NCCC), well supported by a collaborative team including medical oncologist, surgeon, dermatologist and immunologist. The Sponsor’s lab houses expertise in tumor immunology, memory T cell and translational research and the sponsor has rich experiences in mentoring graduate students. The trainings will be focused on knowledge and novel technical skills such as the 10X spatial transcriptomics to successfully finish the research project. In addition, developing professionals for the transition to the K00 phase is also an important training objective. Transitioning to the K00 phase, the research focus will be cancer immunotherapy resistance mechanisms and the development of novel immunotherapeutic strategies that leverage microbiome. Intratumoral microbiomes were recently found to promote successful tumor immunity even in ‘immune-cold’ cancer types, yet the exact molecular and cellular mechanisms remain unknown. I hypothesize that certain microbiomes could reprogram immune cells and the tumor cells themselves, leading to a more proinflammatory anti-tumor microenvironment. The research will be conducted in an outstanding cancer immunology lab combining leaderships in both translational human research and mechanistic fundamental studies in pre-clinical models. The research trainings will be focused on using mouse models, genomics, epigenomics, metabolomics and cellular immunology approaches to identify the critical mechanisms to overcome immunotherapy resistant cancer growth. The goal by the end of the F99/K00 trainings is to understand the features of tumor protective immune responses and the optimal design of novel cancer immunotherapies. These trainings will provide critical knowledge and skills for the ultimate career goal to establish a research group in academia focusing on developing successful immunotherapeutic regimens.