CD169+ macrophages orchestrate anti-tumor CD8+ T cell immunity in a preclinical model of breast cancer 3914

Abstract Description We explore how CD169+ macrophages (MP) and CD8+ T cells coordinate effective anti-tumor immunity in a breast cancer model where mammary stem cells harbor the three cancer driver mutations most frequently associated in human patients (Tp53-/-, MLL3-/-, and PIK3CA). Flow cytometry analysis and tissue section imaging revealed that CD169+F4/80+ MP rapidly infiltrated and outnumbered all other immune cell populations during tumor growth, suggesting they were likely to play an instrumental role in shaping the tumor microenvironment. Selective depletion of these MP in tumor bearing mice resulted in significantly accelerated tumor growth and significantly lower production of effector cytokines (TNF, IFNγ, CCL3) by CD8+ T cells compared to the non-depleted control group. When we deleted STING signaling in CD169+ MP, disrupting a pathway involved in sensing double stranded DNA and producing type I interferon, we also observed faster tumor growth, lower effector function in T cells, and decreased cell surface expression of the integrin CD103 that is associated with tissue residency. Consistent with this result, multiplex immunofluorescent imaging analysis indicated that CD8+ T cells were more clustered in tumors from mice with STING deficient MP. Overall, our data provide evidence for a therapeutically targetable mechanism for aggressive breast cancer in which STING sensing in tumor infiltrating CD169+ MP results in the production of Type I interferons to activate effector CD8+ T cells. Funding Sources DOD BC200410, NIH R21 CA290322 Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)