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

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 Tcells (Tex) in the TME is extensively linked. We demonstrate that invivo depletion of TAMs reduces exhaustion programs in tumor-infiltrating CD8+ Tcells 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+ Tcells engage in unique, long-lasting, antigen-specific synaptic interactions that fail to activate Tcells 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.