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

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 (Tex)
in the TME are 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 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.