TY - JOUR
T1 - The Conventional Dendritic Cell 1 Subset Primes CD8+ T Cells and Traffics Tumor Antigen to Drive Antitumor Immunity in the Brain
AU - Bowman-Kirigin, Jay A.
AU - Desai, Rupen
AU - Saunders, Brian T.
AU - Wang, Anthony Z.
AU - Schaettler, Maximilian O.
AU - Liu, Connor J.
AU - Livingstone, Alexandra J.
AU - Kobayashi, Dale K.
AU - Durai, Vivek
AU - Kretzer, Nicole M.
AU - Zipfel, Gregory J.
AU - Leuthardt, Eric C.
AU - Osbun, Joshua W.
AU - Chicoine, Michael R.
AU - Kim, Albert H.
AU - Murphy, Kenneth M.
AU - Johanns, Tanner M.
AU - Zinselmeyer, Bernd H.
AU - Dunn, Gavin P.
N1 - Funding Information:
We acknowledge the Immune Monitoring Laboratory (particularly Diane Bender) and Washington University Department of Pathology Flow Cytometry Core for flow cytometer and instrumentation support. We acknowledge David DeNardo, Gwendalyn Randolph, Josh Rubin, Morey Blinder, and Robert Schreiber for their incisive input. We thank Matthew Holt for his superb illustrations. This study was supported by the National Institutes of Health NINDS grant R01NS112712 and Cancer Research Institute Lloyd J. Old STAR Award (to G.P. Dunn), National Institutes of Health NCI grant F30CA236454 (to J.A. Bowman-Kirigin).
Funding Information:
N.M. Kretzer reports grants from Howard Hughes during the conduct of the study as well as personal fees from GOG Foundation/Immunogen outside the submitted work. E.C. Leuthardt reports other support from Neurolutions outside the submitted work. A.H. Kim reports other support from Monteris Medical, and grants from Stryker and Collagen Matrix outside the submitted work. G.P. Dunn reports personal fees from Ziopharm Oncology and other support from Immu-novalent Therapeutics outside the submitted work. No disclosures were reported by the other authors.
Publisher Copyright:
©2022 American Association for Cancer Research.
PY - 2023/1/1
Y1 - 2023/1/1
N2 - The central nervous system (CNS) antigen-presenting cell (APC) that primes antitumor 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; cDCs 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 (GBM) models and cDC1-deficient mice, we explored the presently unknown role of cDC1 in CNS antitumor 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 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 GBM resection. Together, these data elucidate the specialized behavior of cDC1 and suggest that cDC1 play a significant role in CNS antitumor immunity.
AB - The central nervous system (CNS) antigen-presenting cell (APC) that primes antitumor 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; cDCs 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 (GBM) models and cDC1-deficient mice, we explored the presently unknown role of cDC1 in CNS antitumor 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 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 GBM resection. Together, these data elucidate the specialized behavior of cDC1 and suggest that cDC1 play a significant role in CNS antitumor immunity.
UR - http://www.scopus.com/inward/record.url?scp=85145492005&partnerID=8YFLogxK
U2 - 10.1158/2326-6066.CIR-22-0098
DO - 10.1158/2326-6066.CIR-22-0098
M3 - Article
C2 - 36409838
AN - SCOPUS:85145492005
SN - 2326-6066
VL - 11
SP - 20
EP - 27
JO - Cancer immunology research
JF - Cancer immunology research
IS - 1
ER -