RT Journal Article SR Electronic T1 Spatiotemporal co-dependency between macrophages and exhausted CD8+ T cells in cancer JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.09.27.461866 DO 10.1101/2021.09.27.461866 A1 Kelly Kersten A1 Kenneth H. Hu A1 Alexis J. Combes A1 Bushra Samad A1 Tory Harwin A1 Arja Ray A1 Arjun Arkal Rao A1 En Cai A1 Kyle Marchuk A1 Jordan Artichoker A1 Tristan Courau A1 Quanming Shi A1 Julia Belk A1 Ansuman T. Satpathy A1 Matthew F. Krummel YR 2021 UL http://biorxiv.org/content/early/2021/09/28/2021.09.27.461866.abstract AB 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.Competing Interest StatementM.F.K. is a founder, and shareholder in Pionyr Immunotherapeutics and in Foundery Innovations, that prosecute and develop novel immunotherapeutics respectively.