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

Kelly Kersten; Kenneth H Hu; Alexis J Combes; Bushra Samad; Tory Harwin; Arja Ray; Arjun Arkal Rao; En Cai; Kyle Marchuk; Jordan Artichoker; Tristan Courau; Quanming Shi; Julia Belk; Ansuman T Satpathy; Matthew F Krummel

doi:10.1016/j.ccell.2022.05.004

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

Cancer Cell. 2022 Jun 13;40(6):624-638.e9. doi: 10.1016/j.ccell.2022.05.004. Epub 2022 May 26.

Authors

Affiliations

¹ 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.
² 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.
³ 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.
⁴ UCSF CoLabs, University of California, San Francisco, San Francisco, CA 94143, USA.
⁵ Department of Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁶ Department of Computer Science, Stanford University, Stanford, CA 94305, USA.
⁷ 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.
⁸ 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: [email protected].

Abstract

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.

Keywords: T cell exhaustion; antitumor immunity; immunotherapy; tumor microenvironment; tumor-associated macrophages.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

CD8-Positive T-Lymphocytes*
Cell Differentiation
Humans
Macrophages
Neoplasms* / genetics
Tumor Microenvironment

Abstract

Publication types

MeSH terms

Grants and funding