Spatiotemporal co-dependency between macrophages and exhausted CD8 + T cells in cancer.

Autor: Kersten K; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA., Hu KH; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA., Combes AJ; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA., Samad B; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA., Harwin T; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA., Ray A; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA., Rao AA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA., Cai E; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA., Marchuk K; UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA., Artichoker J; UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA., Courau T; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA., Shi Q; Department of Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA., Belk J; Department of Computer Science, Stanford University, Stanford, CA 94305, USA., Satpathy AT; Department of Pathology, Stanford University, Stanford, CA 94305, USA; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA., Krummel MF; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; ImmunoX Initiative, University of California, San Francisco, San Francisco, CA 94143, USA; UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA. Electronic address: matthew.krummel@ucsf.edu.
Jazyk: angličtina
Zdroj: Cancer cell [Cancer Cell] 2022 Jun 13; Vol. 40 (6), pp. 624-638.e9. Date of Electronic Publication: 2022 May 26.
DOI: 10.1016/j.ccell.2022.05.004
Abstrakt: T cell exhaustion is a major impediment to antitumor immunity. However, it remains elusive how other immune cells in the tumor microenvironment (TME) contribute to this dysfunctional state. Here, we show that the biology of tumor-associated macrophages (TAMs) and exhausted T cells (T ex ) in the TME is extensively linked. We demonstrate that in vivo depletion of TAMs reduces exhaustion programs in tumor-infiltrating CD8 + T cells and reinvigorates their effector potential. Reciprocally, transcriptional and epigenetic profiling reveals that T ex express factors that actively recruit monocytes to the TME and shape their differentiation. Using lattice light sheet microscopy, we show that TAM and CD8 + T cells engage in unique, long-lasting, antigen-specific synaptic interactions that fail to activate T cells but prime them for exhaustion, which is then accelerated in hypoxic conditions. Spatially resolved sequencing supports a spatiotemporal self-enforcing positive feedback circuit that is aligned to protect rather than destroy a tumor.
Competing Interests: Declaration of interests A.T.S. is a scientific founder of Immunai and founder of Cartography Biosciences and receives research funding from Merck Research Laboratories and Allogene Therapeutics. M.F.K. is a founder and shareholder in Pionyr Immunotherapeutics and in Foundery Innovations, which prosecute and develop novel immunotherapeutics, respectively. The other authors declare no competing interests.
(Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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