Building on data in 20 patients with RCC that Tex cell marker expression was associated with monocyte/macrophage differentiation, Kersten et al. showed in mice that depleting TAMs increased CD8+ TIL effector function, while depleting CD8+ T cells increased pro-tumorigenic marker expression on TAMs. Ex vivo, mouse Tex cells expressed regulators of monocyte/macrophage migration and function. Lattice light sheet microscopy and calcium imaging showed sustained antigen-specific TAM–CD8+ T cell synaptic interactions that induced T cell exhaustion, which was exacerbated by hypoxia. Spatial transcriptomics localized TAMs and CD8+ Tex cells to the more hypoxic inner TME.
Contributed by Paula Hochman
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.