Aire-expressing macrophages as novel mediators of tumor immune evasion

/Abstract Immunotherapy has revolutionized the treatment of cancer, but many malignancies remain resistant to these interventions. Defining novel mechanisms by which tumors evade immune responses is therefore of critical importance. While extensive work has focused on effector and regulatory T-cell populations in tumors and their roles in the tumor microenvironment (TME), less attention has been paid to the myeloid antigen-presenting populations that shape these immune responses. Several studies have demonstrated the crucial role of macrophages in shaping the TME, tumor immunity and response to immunotherapy. However, treatments targeting them have lagged behind T-cell directed therapies like immune checkpoint blockade (ICB) as we still lack a complete understanding of the molecular and functional diversity of the tumor macrophage compartment. We have previously defined novel tolerogenic populations of antigen-presenting cells outside of the thymus characterized by expression of the Autoimmune Regulator (Aire) gene which play critical roles in immune tolerance and homeostasis. We have demonstrated that such extrathymic Aire-expressing cells (eTACs) are essential for the maintenance of maternal-fetal immune tolerance, and may govern commensal-specific peripheral regulatory T cell development. In addition, we have recently discovered that Aire expressing tumor-associated macrophages (Aire+ TAMs) are present in mouse and human cancers. In mice, a broad range of tumors induce or recruit Aire+ TAMs. Selective ablation of this population significantly reduces tumor growth and, strikingly, converts ICB-resistant tumors into ICB- sensitive ones in a manner dependent on CD8 T cells. We hypothesize that Aire+ TAMs constitute novel populations of tolerogenic innate immune cells with critical roles in tumor immune evasion, and represent entirely new targets with broad therapeutic potential for cancer immunotherapy. Our aims are to define the identity and role of Aire+ TAMs in tumor immune evasion across a range of murine cancer models and human cancers, delineate the functional and mechanistic role of Aire itself in these populations, and define the cellular and molecular mechanisms of Aire+ TAM-mediated tumor immune evasion. We believe that defining the biology and function of these populations could present numerous therapeutic opportunities with transformative potential in tumor immunotherapy. Project Number: 1R37CA304094-01 | Fiscal Year: 2025 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: James Gardner | Institution: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, SAN FRANCISCO, CA | Award Amount: $677,787 | Activity Code: R37 | Study Section: Basic Cancer Immunobiology Study Section[BCIB] View on NIH RePORTER: https://reporter.nih.gov/project-details/11209733