Paper Readig
01
Treg Cells Promotethe SREBP1-Dependent Metabolic Fitness of Tumor-Promoting Macrophages via Repression of CD8+ T Cell-Derived Interferon-γ
Chang Liu, MariaChikina, et al.
Immunity,
In this paper, the authors found that in tumor microenvironment Treg cells maintaintheir immunosuppressive effects on multiple cell types, particularly M2-like TAMsthat in turn increase their tumor occupancy (cell density) and enhance theirpro-tumor metabolic function. Intratumoral Treg cells promote M2-like TAMsindirectly by limiting IFNg production by CD8+ T cells, which would otherwiseundermine M2-like TAM development and function. Besides, Treg cells also can limitthe SRC of M1-like TAMs, and thus potentiate their metabolic capacity via IFNg repression.Their analysis also reveals that activation of SREBP1-depend de novo fatty acidsynthesis is one of the key sources of cellular fatty acids that feed intothese metabolic processes and its regulation in the TME remain elusivesuggesting that targeting the SREBP1pathway may be an effective immunotherapeutic strategy. FFA depletion wascoupled to enhanced mitochondrial depolarization in the TAMs from Nrp1L/LFoxp3Cre-YFPmice, particularly in the M2-like subset, as a result of defective SREBP1 upregulation. TAMs from Nrp1L/LFoxp3Cre-YFP mice exhibited enhanced expression of ER stress-related genes accompanied by increased mitochondrial ROS production which contributed to the CD8+ Tcell/IFNg dependent mitochondrial damage and cell death observed in M2-likeTAMs. Further analysis suggested that two impacts of IFNg activity: (1)restraining baseline M2-like TAMs polarization, which was independent of tumorburden; and (2) depleting the TAM compartment with selectivity toward theM2-like phenotype, under the setting of effective immunotherapy or substantiveloss of Treg cell suppression.
In summary, this paper indicated that intratumoral Treg cells orchestrate multifaceted immunosuppression of the TME via at least two interconnected mechanisms: (1) direct inhibition of anti-tumor CD8+ and CD4+ T cells; and (2)promotion of the metabolic fitness of pro-tumor M2-like TAMs, indirectly viaCD8+ T cells.
https://sci-hub.tw//immunity/fulltext/S1074-7613(19)30287-0?rss=yes
02
A Single-Cell Atlas of the Tumor and Immune Ecosystem of Human Breast Cancer
JohannaWagner,MariaAnna Rapsomaniki, et al.
Cell，
Communication between heterogeneous tumor cells, infiltrating Tcells, and macrophages shapes the breast cancer ecosystem, with an effect ondisease progression and clinical outcome. In this paper, the researchers constructed anextensive single-cell atlas of human breast cancer ecosystems bylarge-scale mass cytometry profiling of 26 million cells from 144 tumor samples, 46 juxta-tumoral samples, and tissue from four reductionmammoplasties. They found that PD-1+ T cells and PD-L1+ TAMs were common in allbreast cancer subtypes while Receptors relevant to T cell exhaustion (PD-1, CTLA-4,and TIM-3) and activation (HLA-DR and CD38) as well as CD38, pro-tumor (CD204,CD206, and CD163), and anti-tumor TAM markers (CD169) were heterogeneously expressed. They also found different combinations of immune checkpoint molecules associated with high PD-1 expression in both CD4+ and CD8+ T cell populations and identified CD38 as a marker of T cell exhaustion in breast cancer. Further analysis showed that 18% of luminal B tumor samples exhibited patterns of strong T cellexhaustion akin to ER- tumors, suggesting that some ER+ patients could benefit from neoadjuvant or early adjuvant anti-PD-1 and anti-PD-L1 therapy targeting the primary tumor.
/10.1016/j.cell..03.005
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