Th149 - Aire-expressing Tumor-associated Macrophages Promote Cancer Immune Evasion

Jing-Yi Chung – University of California San Francisco; Kade Copple – University of California San Francisco; James Gardner – University of California San Francisco; Joe Germino – University of California San Francisco; Matthew Krummel – University of California San Francisco; Arja Ray – University of California San Francisco; Matthew Spitzer – University of California San Francisco; Im-Hong Sun – University of California San Francisco; Jiaxi Wang – University of California San Francisco; Sophia Guldberg – University of California San Francisco; Alexander Gupta – University of California San Francisco; Nolan Horner – University of California San Francisco; Han Yin – University of California San Francisco

Abstract Text: Peripheral immune populations expressing the Autoimmune Regulator (Aire) gene have been suggested to play critical roles in immune self-education, maternal-fetal tolerance, and commensal tolerance in the gut, but their roles have not been defined in the tumor microenvironment (TME). TMEs are populated by highly heterogenous myeloid populations with either tolerogenic or anti-tumor properties. Understanding the immunosuppressive programs that promote tumor tolerance in myeloid populations could lead to new therapeutic targeting strategies. Here we demonstrate the presence of Aire-expressing macrophages (aTAMs) across multiple mouse tumor models (MC38 and B16F10) and characterize them as an immunosuppressive, tumor-promoting macrophage subtype. These aTAMs display a unique transcriptional and metabolic profile characterized by increased immunosuppressive and proliferative features. The Aire gene is central to the formation of these aTAMs, as Aire-deficient mice exhibit a decrease in the aTAM population and in the gene signature that characterizes this cell population. Ablation of aTAMs (Aire-DTR) improves tumor control across multiple immunotherapy-resistant tumor models in a CD8 T cell-dependent manner resulting in increased CD8 T cell activation and inflammatory remodeling of the myeloid compartment. Notably, peripheral loss of Aire (Vav1-Cre x Airefl/fl) or aTAM ablation (Aire-DTR) synergizes with anti-PD-1 to improve anti-tumor immunity demonstrating a previously undiscovered role of extrathymic Aire. Furthermore, aTAMs can be found in human scRNA-seq tumor datasets across multiple tumor types and are associated with poor prognosis. Our data identify a novel macrophage population and demonstrate that extrathymic Aire in this phenotypically and functionally distinct population plays a critical role in inhibiting anti-tumor immunity.