AIRE is expressed in breast cancer TANs and TAMs to regulate the extrinsic apoptotic pathway and inflammation.

The autoimmune regulator (AIRE) is a transcriptional regulator expressed in the thymus and is necessary for maintaining immunological self-tolerance. Extrathymic AIRE expression is rare, and a role for AIRE in tumor-associated innate immune cells has not yet been established. In this study, we show that AIRE is expressed in human pro-tumor neutrophils. In breast cancer, AIRE was primarily located to tumor-associated neutrophils (TANs), and to a lesser extent to tumor-associated macrophages (TAMs) and tumor cells. Expression of AIRE in TAN/TAMs, but not in cancer cells, was associated with an adverse prognosis. We show that the functional role for AIRE in neutrophils and macrophages is to regulate expression of immune mediators and the extrinsic apoptotic pathway involving the Fas/TNFR death receptors and cathepsin G. Here, we propose that the role for AIRE in TAN/TAMs in breast tumors is to regulate cell death and inflammation, thus promoting tumor progression.

Human G-MDSCs are neutrophils at distinct maturation stages promoting tumor growth in breast cancer.

Myeloid-derived suppressor cells (MDSCs) are known to contribute to immune evasion in cancer. However, the function of the human granulocytic (G)-MDSC subset during tumor progression is largely unknown, and there are no established markers for their identification in human tumor specimens. Using gene expression profiling, mass cytometry, and tumor microarrays, we here demonstrate that human G-MDSCs occur as neutrophils at distinct maturation stages, with a disease-specific profile. G-MDSCs derived from patients with metastatic breast cancer and malignant melanoma display a unique immature neutrophil profile, that is more similar to healthy donor neutrophils than to G-MDSCs from sepsis patients. Finally, we show that primary G-MDSCs from metastatic breast cancer patients co-transplanted with breast cancer cells, promote tumor growth, and affect vessel formation, leading to myeloid immune cell exclusion. Our findings reveal a role for human G-MDSC in tumor progression and have clinical implications also for targeted immunotherapy.