The Center for Tumor-Immune Systems Biology at MSKCC

MSKCC肿瘤免疫系统生物学中心 摘要 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 护理多种实体肿瘤类型，并展示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 癌症，即使在ICB现在是标准护理的肿瘤中，也只有一小部分患者能够持久 填写完整的回复。解决这些限制需要(1)提高我们对 当前免疫疗法失败的免疫学背景下的肿瘤-免疫相互作用和(2)发展 在仅取得部分成功的情况下加强应对的新战略。该中心为 MSKCC的肿瘤免疫系统生物学已经组建了一个由领先研究人员组成的多学科团队 在计算生物学、免疫学和癌症生物学方面应对这些挑战。该中心是有组织的 大约三个研究项目，将计算和实验研究整合在小鼠模型和 在免疫治疗抵抗和应答两种情况下的患者肿瘤的分子分析，开拓新的 使用共聚焦的单细胞多组、高复用化光学成像的机器学习建模 免疫荧光和空间转录数据集。我们将调查不同的免疫系统 癌症对ICB难治性的微环境：脑转移定植，免疫- 癌细胞、星形胶质细胞和不同疾病状态相互作用的特权器官 小胶质细胞决定了侵袭模式(项目I)；错配修复熟练的原发结肠癌，其中 肿瘤存在于耐受的微环境中，并与复杂的细胞回路相互作用。 传统T细胞，以及向淋巴结和肝脏转移(项目II)。我们还将开展一项 ICB反应性黑色素瘤模型中癌细胞死亡机制的系统生物学询问 肾细胞癌，基于研究发现，工程线粒体损伤依赖，但caspase- 独立细胞死亡引起抗癌免疫和防止肿瘤再挑战(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。这些研究将取得进展 我们对ICB-难耐微环境中的肿瘤免疫生态系统的基本理解 ICB反应环境中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 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的研究。我们的 研究中心还将开展创新的外联和培训活动，以传播研究成果 在肿瘤免疫系统生物学方面，并培训这一关键领域的年轻科学家。

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.