The Center for Tumor-Immune Systems Biology at MSKCC

MSKCC 肿瘤免疫系统生物学中心

基本信息

批准号：
10525190
负责人：
Christina S Leslie
金额：
$ 265.5万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-16 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10525190
关键词：
Address Algorithmic Analysis Anti-Inflammatory Agents Astrocytes Award Brain CD8-Positive T-Lymphocytes Cancer Biology Cancer Center Caspase Cell Death Cells Chromatin Clear cell renal cell carcinoma Colon Carcinoma Complex Computational Biology Computing Methodologies Data Data Set Dendritic Cells Development Disease associated microglia Distal Ecosystem Education and Outreach Educational workshop Engineering Functional disorder Genetic Transcription Human Immune Immune response Immune system Immunofluorescence Immunologic Immunological Models Immunologics Immunology Immunotherapeutic agent Immunotherapy In complete remission Investigation Ligands Link Liver Lung Adenocarcinoma Malignant Neoplasms Mediating Melanoma Cell Memorial Sloan-Kettering Cancer Center Metastatic Neoplasm to Lymph Nodes Metastatic Neoplasm to the Leptomeninges Methods Mismatch Repair Mitochondria Modality Modeling Molecular Analysis Organ Patients Process Refractory Regulator Genes Renal Cell Carcinoma Research Research Personnel Research Project Grants Resistance Resource Sharing Role Scientific Advances and Accomplishments Scientist Solid Neoplasm System Systems Biology T cell response T memory cell T-Lymphocyte Technology Therapeutic Training Training Activity Training Programs Tumor Immunity anti-cancer base cancer care cancer cell cancer immunotherapeutics cancer immunotherapy clinical care colorectal cancer metastasis computer studies design experimental study graduate student immune checkpoint blockade immunogenic immunogenic cell death improved innovation insight learning strategy lectures machine learning model malignant breast neoplasm mouse model multidisciplinary novel novel strategies optical imaging programs receptor refractory cancer response standard of care success symposium tissue regeneration tool transcriptomics tumor tumor immunology tumor-immune system interactions undergraduate student

项目摘要

The Center for Tumor-Immune Systems Biology at MSKCC SUMMARY The advent of cancer immunotherapies based on immune checkpoint blockade (ICB) has revolutionized clinical care in multiple solid tumor types and demonstrated the power of the immune system to target and eliminate cancer cells. Despite these breakthroughs, the efficacy of ICB-based immunotherapy is limited to a subset of cancers, and even in tumors where ICB is now the standard of care, only a fraction of patients achieve durable complete responses. Addressing these limitations requires (1) improving our fundamental understanding of tumor-immune interactions in immunological contexts where current immunotherapies fail and (2) developing novel strategies for enhancing responses in contexts where they have only partial success. The Center for Tumor-Immune Systems Biology at MSKCC has assembled a multi-disciplinary team of leading investigators in computational biology, immunology, and cancer biology to tackle these challenges. The Center is organized around three Research Projects that integrate computational and experimental studies in mouse models and molecular analyses in patient tumors in both immunotherapy-resistant and -responsive contexts, exploiting novel machine learning modeling of single-cell multiome, highly multiplexed optical imaging using confocal immunofluorescence, and spatial transcriptomic data sets. We will investigate distinct immune microenvironments where cancers are refractory to ICB: metastatic colonization of the brain, an immune- privileged organ where the interplay of cancer cells, astrocytes, and different states of disease-associated microglia dictate modes of invasion (Project I); and mismatch-repair proficient primary colon cancer, where tumors reside in a tolerizing microenvironment and interact with complex cellular circuits of regulatory and conventional T cells, together with metastases to the lymph node and liver (Project II). We will also carry out a systems biology interrogation of cancer cell death mechanisms in models of ICB-responsive melanoma and renal cell carcinoma, based on findings that engineering mitochondrial damage-dependent but caspase- independent cell death elicits anti-cancer immunity and protection against tumor rechallenge (Project III). A Shared Resource Core will interact with all three Research Projects to develop computational methods and establish technologies for spatial analyses of the tumor-immune microenvironment. These studies will advance our fundamental understanding of tumor-immune ecosystems in ICB-refractory microenvironments and of immune responses to therapeutically induced immunogenic cancer cell death in ICB-responsive settings, ultimately leading to novel immunotherapeutic targets and combination strategies. Our team will build on the successes of our previous CSBC U54 Center award for the Center for Cancer Systems Immunology at MSKCC, which produced numerous high-impact studies at the forefront of systems biology and cancer immunology. Our Research Center will also carry out innovative outreach and training activities to disseminate research findings in tumor-immune systems biology and to train young scientists in this critical field.

MSKCC 肿瘤免疫系统生物学中心概括基于免疫检查点阻断（ICB）的癌症免疫疗法的出现彻底改变了临床对多种实体瘤类型进行护理，并证明了免疫系统靶向和消除的能力癌细胞。尽管取得了这些突破，但基于 ICB 的免疫疗法的疗效仅限于一小部分患者。癌症，甚至在 ICB 现在成为护理标准的肿瘤中，也只有一小部分患者能够实现持久治疗完整的答复。解决这些局限性需要 (1) 提高我们对当前免疫疗法失败的免疫环境中的肿瘤-免疫相互作用以及（2）正在发展在只取得部分成功的情况下加强反应的新策略。该中心 MSKCC 的肿瘤免疫系统生物学组建了一支由领先研究人员组成的多学科团队计算生物学、免疫学和癌症生物学领域的研究人员来应对这些挑战。该中心已组织围绕三个研究项目，将小鼠模型中的计算和实验研究结合起来在免疫治疗耐药和应答的情况下对患者肿瘤进行分子分析，利用新的方法使用共聚焦的单细胞多组学、高度多重光学成像的机器学习建模免疫荧光和空间转录组数据集。我们将研究不同的免疫癌症对 ICB 耐药的微环境：大脑的转移性定植，一种免疫- 癌细胞、星形胶质细胞和疾病相关的不同状态相互作用的特殊器官小胶质细胞决定入侵模式（项目 I）；和错配修复熟练的原发性结肠癌，其中肿瘤存在于耐受性微环境中，并与复杂的细胞调节和调节回路相互作用。传统 T 细胞，以及淋巴结和肝脏转移（项目 II）。我们还将开展 ICB 反应性黑色素瘤模型中癌细胞死亡机制的系统生物学研究肾细胞癌，基于工程线粒体损伤依赖性但半胱天冬酶- 独立的细胞死亡可引发抗癌免疫并防止肿瘤再攻击（项目 III）。一个共享资源核心将与所有三个研究项目互动，以开发计算方法和建立肿瘤免疫微环境的空间分析技术。这些研究将推进我们对 ICB 难治性微环境中的肿瘤免疫生态系统的基本了解在 ICB 反应环境中对治疗诱导的免疫原性癌细胞死亡的免疫反应，最终导致新的免疫治疗靶点和组合策略。我们的团队将在此基础上我们之前为 MSKCC 癌症系统免疫学中心颁发的 CSBC U54 中心奖的成功，它在系统生物学和癌症免疫学的前沿产生了许多高影响力的研究。我们的研究中心还将开展创新的外展和培训活动，以传播研究成果肿瘤免疫系统生物学领域的研究，并培训这一关键领域的年轻科学家。