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Spatiotemporal Co-Dependency between Macrophages and Exhausted CD8 + T Cells in Cancer

55 Pages Posted: 13 Oct 2021 Publication Status: Published

See all articles by Kelly Kersten

Kelly Kersten

University of California, San Francisco (UCSF) - Department of Pathology

Kenneth H. Hu

University of California, San Francisco (UCSF) - Department of Pathology; University of California, San Francisco (UCSF) - Department of Pathology

Alexis J. Combes

University of California, San Francisco (UCSF) - Department of Pathology

Bushra Samad

University of California, San Francisco (UCSF) - Department of Pathology

Tory Harwin

University of California, San Francisco (UCSF) - Department of Pathology

Arja Ray

University of California, San Francisco (UCSF) - Department of Pathology

Arjun Arkal Rao

University of California, San Francisco (UCSF) - Department of Pathology

En Cai

University of California, San Francisco (UCSF) - Department of Pathology

Kyle Marchuk

University of California, San Francisco (UCSF) - UCSF CoLabs

Jordan Artichoker

University of California, San Francisco (UCSF) - UCSF CoLabs

Tristan Courau

University of California, San Francisco (UCSF) - Department of Pathology

Quanming Shi

Stanford University - Department of Personal Dynamic Regulomes

Julia Belk

Stanford University - Department of Computer Science

Ansuman T. Satpathy

Stanford University - Department of Pathology

Matthew F. Krummel

University of California, San Francisco (UCSF) - Department of Pathology

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Abstract

T cell exhaustion is a major impediment to anti-tumor 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 (TAM) and exhausted T cells (Tex) in the TME is extensively linked. We demonstrate that in vivo depletion of TAM reduces exhaustion programs in tumor-infiltrating CD8+ T cells and reinvigorates their effector potential. Reciprocally, transcriptional and epigenetic profiling reveals that Tex 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: tumor-associated macrophages, tumor microenvironment, T cell exhaustion, anti-tumor immunity, Immunotherapy

Suggested Citation

Kersten, Kelly and Hu, Kenneth H. and Combes, Alexis J. and Samad, Bushra and Harwin, Tory and Ray, Arja and Rao, Arjun Arkal and Cai, En and Marchuk, Kyle and Artichoker, Jordan and Courau, Tristan and Shi, Quanming and Belk, Julia and Satpathy, Ansuman T. and Krummel, Matthew F., Spatiotemporal Co-Dependency between Macrophages and Exhausted CD8 + T Cells in Cancer. Available at SSRN: https://ssrn.com/abstract=3942126 or http://dx.doi.org/10.2139/ssrn.3942126
This version of the paper has not been formally peer reviewed.

Kelly Kersten

University of California, San Francisco (UCSF) - Department of Pathology ( email )

San Francisco, CA 94143
United States

Kenneth H. Hu

University of California, San Francisco (UCSF) - Department of Pathology ( email )

San Francisco, CA 94143
United States

University of California, San Francisco (UCSF) - Department of Pathology ( email )

San Francisco, CA 94143
United States

Alexis J. Combes

University of California, San Francisco (UCSF) - Department of Pathology ( email )

San Francisco, CA 94143
United States

Bushra Samad

University of California, San Francisco (UCSF) - Department of Pathology ( email )

San Francisco, CA 94143
United States

Tory Harwin

University of California, San Francisco (UCSF) - Department of Pathology ( email )

San Francisco, CA 94143
United States

Arja Ray

University of California, San Francisco (UCSF) - Department of Pathology ( email )

San Francisco, CA 94143
United States

Arjun Arkal Rao

University of California, San Francisco (UCSF) - Department of Pathology ( email )

San Francisco, CA 94143
United States

En Cai

University of California, San Francisco (UCSF) - Department of Pathology ( email )

San Francisco, CA 94143
United States

Kyle Marchuk

University of California, San Francisco (UCSF) - UCSF CoLabs ( email )

San Francisco, CA
United States

Jordan Artichoker

University of California, San Francisco (UCSF) - UCSF CoLabs ( email )

San Francisco, CA
United States

Tristan Courau

University of California, San Francisco (UCSF) - Department of Pathology ( email )

San Francisco, CA 94143
United States

Quanming Shi

Stanford University - Department of Personal Dynamic Regulomes ( email )

Stanford, CA
United States

Julia Belk

Stanford University - Department of Computer Science ( email )

Gates Computer Science Building
353 Serra Mall
Stanford, CA 94305-9025
United States

Ansuman T. Satpathy

Stanford University - Department of Pathology ( email )

291 Campus Drive
Li Ka Shing Building
Stanford, CA 94305-5101
United States

Matthew F. Krummel (Contact Author)

University of California, San Francisco (UCSF) - Department of Pathology ( email )

San Francisco, CA 94143
United States

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