UCSF

Immune checkpoint blockade (ICB) therapies have enhanced patient survival in a variety of cancers, but many patients still do not durably respond to ICB. Failure to mount a successful immune response has been attributed to a variety of factors including immune exclusion, tumor burden, and immunosuppressive tumor microenvironments (TME). Tumor-associated macrophage (TAM) abundance is often correlated with an immunosuppressive TME and ICB resistance. Surprisingly, TAM-targeted therapies such as anti-CSF1R blockade have had disappointing results in the clinic. This emphasizes a need to better understand the complexities of the TME and the divergent roles that TAMs can have. Here, we establish a role for TAMs in altering the composition of the TME with differential tumor burden and in the context of ICB. Importantly, ICB at low tumor burdens was capable of inflammatory remodeling of the TAM compartment. Using novel transgenic mouse models, this study explores how Aire-expressing tumor-associated macrophages (aTAMs) support an immunosuppressive TME in a CD8 T cell-dependent fashion. aTAM depletion or macrophage-specific Aire deficiency significantly improves ICB responses. Further, we have used publicly available human cancer datasets to explore the paradoxical inflammatory T cell circuit present in ICB treatment of IL1R1-expressing tumors. Taken together, these studies advance our understanding of the immunosuppressive immune dynamics of the TME particularly those relevant to modulating TAMs.