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

项目概要/摘要： 在过去的十年中，检查点阻断免疫疗法大大改善了患者的总体生存率。 晚期黑色素瘤患者然而，这些疗法未能治疗许多其他癌症类型，包括 胰腺癌肝癌和胃癌了解成功的肿瘤保护性免疫反应 在长期癌症幸存者可以促进抗肿瘤免疫反应的理解， 开发新的治疗策略。发生皮肤免疫相关不良反应的黑素瘤患者 包括皮疹和白癜风在内的irAE患者的总体生存率高于未受影响的患者。然而，在这方面， 将皮肤irAE与特殊的抗肿瘤免疫联系起来的免疫机制仍然未知。因此，在本发明中， 特异性目标1将全面表征表型、持久性、抗原特异性和定位 白癜风和皮疹影响的黑色素瘤幸存者中的抗肿瘤T细胞应答， 单细胞TCR-seq、批量TCR-seq和10 X空间转录组学。我假设与未受影响的相比 在黑色素瘤患者中，皮肤irAE患者维持更持久的促炎性T细胞应答， 肿瘤聚焦TCR库。该项目将在诺里斯-科顿癌症中心（NCCC）进行， 由包括医学肿瘤学家、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。的 申办者的实验室拥有肿瘤免疫学、记忆T细胞和转化研究方面的专业知识， 具有丰富的研究生导师工作经验。培训将侧重于知识和新颖 技术技能，如10 X空间转录组学，以成功完成研究项目。此外，本发明还提供了一种方法， 培养过渡到K 00阶段的专业人员也是一个重要的培训目标。过渡 到K 00阶段，研究重点将是癌症免疫治疗耐药机制和 开发利用微生物组的新型免疫策略。肿瘤内微生物组是 最近发现，即使在“免疫冷”癌症类型中， 细胞机制仍然未知。我假设某些微生物群可以重新编程免疫系统 细胞和肿瘤细胞本身，导致更促炎的抗肿瘤微环境。的 研究将在一个杰出的癌症免疫学实验室进行，该实验室结合了两个翻译领域的领导者， 临床前模型中的人体研究和机械基础研究。研究培训将是 专注于使用小鼠模型，基因组学，表观基因组学，代谢组学和细胞免疫学方法 以确定克服免疫疗法抗性癌症生长的关键机制。到年底的目标是 F99/K 00训练是为了了解肿瘤保护性免疫反应的特点和最佳设计， 新型癌症免疫疗法。这些培训将为最终的职业生涯提供关键的知识和技能 目标是在学术界建立一个研究小组，专注于开发成功的免疫疗法。

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.