Nirschl Christopher J, Suárez-Fariñas Mayte, Izar Benjamin, Prakadan Sanjay, Dannenfelser Ruth, Tirosh Itay, Liu Yong, Zhu Qian, Devi K Sanjana P, Carroll Shaina L, Chau David, Rezaee Melika, Kim Tae-Gyun, Huang Ruiqi, Fuentes-Duculan Judilyn, Song-Zhao George X, Gulati Nicholas, Lowes Michelle A, King Sandra L, Quintana Francisco J, Lee Young-Suk, Krueger James G, Sarin Kavita Y, Yoon Charles H, Garraway Levi, Regev Aviv, Shalek Alex K, Troyanskaya Olga, Anandasabapathy Niroshana
Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Department of Dermatology, Mount Sinai School of Medicine, NY, NY 10029, USA; Department of Genetics and Genomics Sciences Mount Sinai School of Medicine, NY, NY 10029 USA; Population Health Science and Policy, Mount Sinai School of Medicine, NY, NY 10029, USA.
Cell. 2017 Jun 29;170(1):127-141.e15. doi: 10.1016/j.cell.2017.06.016.
Homeostatic programs balance immune protection and self-tolerance. Such mechanisms likely impact autoimmunity and tumor formation, respectively. How homeostasis is maintained and impacts tumor surveillance is unknown. Here, we find that different immune mononuclear phagocytes share a conserved steady-state program during differentiation and entry into healthy tissue. IFNγ is necessary and sufficient to induce this program, revealing a key instructive role. Remarkably, homeostatic and IFNγ-dependent programs enrich across primary human tumors, including melanoma, and stratify survival. Single-cell RNA sequencing (RNA-seq) reveals enrichment of homeostatic modules in monocytes and DCs from human metastatic melanoma. Suppressor-of-cytokine-2 (SOCS2) protein, a conserved program transcript, is expressed by mononuclear phagocytes infiltrating primary melanoma and is induced by IFNγ. SOCS2 limits adaptive anti-tumoral immunity and DC-based priming of T cells in vivo, indicating a critical regulatory role. These findings link immune homeostasis to key determinants of anti-tumoral immunity and escape, revealing co-opting of tissue-specific immune development in the tumor microenvironment.
稳态程序平衡免疫保护和自身耐受。此类机制可能分别影响自身免疫和肿瘤形成。稳态如何维持以及如何影响肿瘤监测尚不清楚。在此，我们发现不同的免疫单核吞噬细胞在分化并进入健康组织的过程中共享一个保守的稳态程序。IFNγ对于诱导该程序是必要且充分的，揭示了其关键的指导作用。值得注意的是，稳态和IFNγ依赖性程序在包括黑色素瘤在内的原发性人类肿瘤中富集，并可对生存进行分层。单细胞RNA测序（RNA-seq）显示人类转移性黑色素瘤的单核细胞和树突状细胞中稳态模块富集。细胞因子-2抑制因子（SOCS2）蛋白是一种保守的程序转录本，由浸润原发性黑色素瘤的单核吞噬细胞表达，并由IFNγ诱导。SOCS2在体内限制适应性抗肿瘤免疫和基于树突状细胞的T细胞启动，表明其具有关键的调节作用。这些发现将免疫稳态与抗肿瘤免疫和逃逸的关键决定因素联系起来，揭示了肿瘤微环境中组织特异性免疫发育的协同作用。
