The Center for Tumor-Immune Systems Biology at MSKCC

MSKCC肿瘤免疫系统生物学中心 总结 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治疗， 治疗多种实体瘤类型，并证明了免疫系统靶向和消除肿瘤的能力。 癌细胞尽管有这些突破，但基于ICB的免疫疗法的疗效仅限于一部分。 癌症，甚至在ICB现在是护理标准的肿瘤中，只有一小部分患者达到持久的治疗效果。 完整的答案。解决这些局限性需要（1）提高我们对 在免疫学背景下的肿瘤-免疫相互作用，其中当前的免疫疗法失败，以及（2）发展中的 在只有部分成功的情况下加强反应的新战略。中心 MSKCC的肿瘤免疫系统生物学已经组建了一个由领先的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中，来应对这些挑战。该中心组织 围绕三个研究项目，整合了小鼠模型的计算和实验研究， 在免疫治疗耐药和免疫治疗反应背景下对患者肿瘤进行分子分析，利用新的 使用共聚焦的单细胞多组高度复用光学成像的机器学习建模 免疫荧光和空间转录组学数据集。我们将研究不同的免疫 癌症对ICB难治的微环境：脑的转移性定植，免疫- 特权器官，其中癌细胞，星形胶质细胞和疾病相关的不同状态的相互作用 小胶质细胞决定侵袭模式（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，并与复杂的调节和 常规T细胞，以及淋巴结和肝脏转移（项目II）。我们亦会进行一项 ICB反应性黑色素瘤模型中癌细胞死亡机制的系统生物学研究 肾细胞癌，基于工程线粒体损伤依赖性，但caspase- 独立的细胞死亡增强抗癌免疫和对肿瘤再攻击的保护（项目III）。一 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， 建立肿瘤免疫微环境空间分析技术。这些研究将进一步 我们对ICB难治性微环境中肿瘤免疫生态系统的基本理解， 在ICB应答环境中对治疗诱导的免疫原性癌细胞死亡的免疫应答， 最终导致新的免疫靶点和组合策略。我们的团队将建立在 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， 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 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和培养年轻科学家在这一关键领域。

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.