Although rare in healthy brain parenchyma, cDC1s and other APCs were found near lymphatic vessels in the dura, infiltrated orthotopic glioblastoma tumors, and trafficked tumor-derived fluorescent antigen to cervical lymph nodes (cLNs). Tumor-specific CD8+ T cells proliferated in cLNs, dura, and tumors, and cDC1-deficient mice had fewer activated and neoantigen-specific CD8+ T cells and reduced anti-PD-L1 responsiveness. APCs were also observed in human brain tumors and dura, with evidence of tumor antigen uptake and local trafficking, detected through a fluorescent metabolite used in the tumor resection.
Contributed by Alex Najibi
ABSTRACT: The central nervous system (CNS) antigen-presenting cell (APC) that primes anti-tumor CD8+ T-cell responses remains undefined. Elsewhere in the body, the conventional dendritic cell 1 (cDC1) performs this role. However, steady-state brain parenchyma cDC1 are extremely rare; cDC localize to the choroid plexus and dura. Thus, whether the cDC1 play a function in presenting antigen derived from parenchymal sources in the tumor setting remains unknown. Using preclinical glioblastoma models and cDC1-deficient mice, we explored the presently unknown role of cDC1 in CNS anti-tumor immunity. We determined that, in addition to infiltrating the brain tumor parenchyma itself, cDC1 prime neoantigen-specific CD8+ T-cells against brain tumors and mediate checkpoint blockade-induced survival benefit. We observed that cDC, including cDC1, isolated from the tumor, the dura, and the CNS-draining cervical lymph nodes (cLNs) harbored a traceable fluorescent tumor antigen. In patient samples, we observed several APC subsets (including the CD141+ cDC1 equivalent) infiltrating glioblastomas, meningiomas, and dura. In these same APC subsets, we identified a tumor-specific fluorescent metabolite of 5-aminolevulinic acid, which fluorescently labeled tumor cells during fluorescence-guided glioblastoma resection. Together, these data elucidate the specialized behavior of cDC1 and suggest cDC1 play a significant role in CNS anti-tumor immunity.
Author Info: (1) Washington University in St. Louis School of Medicine, St. Louis, Missouri, United States. (2) Duke University, Durham, NC, United States. (3) Washington University in St. Loui
Author Info: (1) Washington University in St. Louis School of Medicine, St. Louis, Missouri, United States. (2) Duke University, Durham, NC, United States. (3) Washington University in St. Louis School of Medicine, St. Louis, Missouri, United States. (4) Washington University in St. Louis School of Medicine, St Louis, MO, United States. (5) Washington University in St. Louis School of Medicine, St. Louis, Missouri, United States. (6) Washington University in St. Louis School of Medicine, St. Louis, Missouri, United States. (7) Washington University in St. Louis School of Medicine, St. Louis, MO, United States. (8) Washington University in St. Louis School of Medicine, St. Louis, Missouri, United States. (9) Washington University in St. Louis School of Medicine, St. Louis, Missouri, United States. (10) University of Washington, Seattle, Washington, United States. (11) Washington University in St. Louis School of Medicine, St. Louis, MO, United States. (12) Washington University in St. Louis, St. Louis, Missouri, United States. (13) Washington University in St. Louis, Saint Louis, Missouri, United States. (14) Washington University in St. Louis School of Medicine, St. Louis, Missouri, United States. (15) Washington University in St. Louis School of Medicine, St Louis, MO, United States. (16) Washington University in St. Louis School of Medicine, St. Louis, MO, United States. (17) Washington University in St. Louis School of Medicine, St. Louis, MO, United States. (18) Washington University in St. Louis School of Medicine, St. Louis, MO, United States. (19) Massachusetts General Hospital, Boston, MA, United States.
