PMID- 29509940 OWN - NLM STAT- MEDLINE DCOM- 20191001 LR - 20191008 IS - 1523-5866 (Electronic) IS - 1522-8517 (Print) IS - 1522-8517 (Linking) VI - 20 IP - 8 DP - 2018 Jul 5 TI - Multiplexed immunofluorescence reveals potential PD-1/PD-L1 pathway vulnerabilities in craniopharyngioma. PG - 1101-1112 LID - 10.1093/neuonc/noy035 [doi] AB - BACKGROUND: Craniopharyngiomas are neoplasms of the sellar/parasellar region that are classified into adamantinomatous craniopharyngioma (ACP) and papillary craniopharyngioma (PCP) subtypes. Surgical resection of craniopharyngiomas is challenging, and recurrence is common, frequently leading to profound morbidity. BRAF V600E mutations render PCP susceptible to BRAF/MEK inhibitors, but effective targeted therapies are needed for ACP. We explored the feasibility of targeting the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint pathway in ACP and PCP. METHODS: We mapped and quantified PD-L1 and PD-1 expression in ACP and PCP resections using immunohistochemistry, immunofluorescence, and RNA in situ hybridization. We used tissue-based cyclic immunofluorescence to map the spatial distribution of immune cells and characterize cell cycle and signaling pathways in ACP tumor cells which intrinsically express PD-1. RESULTS: All ACP (15 +/- 14% of cells, n = 23, average +/- SD) and PCP (35 +/- 22% of cells, n = 18) resections expressed PD-L1. In ACP, PD-L1 was predominantly expressed by tumor cells comprising the cyst lining. In PCP, PD-L1 was highly expressed by tumor cells surrounding the stromal fibrovascular cores. ACP also exhibited tumor cell-intrinsic PD-1 expression in whorled epithelial cells with nuclear-localized beta-catenin. These cells exhibited evidence of elevated mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) signaling. Profiling of immune populations in ACP and PCP showed a modest density of CD8+ T cells. CONCLUSIONS: ACP exhibit PD-L1 expression in the tumor cyst lining and intrinsic PD-1 expression in cells proposed to comprise an oncogenic stem-like population. In PCP, proliferative tumor cells express PD-L1 in a continuous band at the stromal-epithelial interface. Targeting PD-L1 and/or PD-1 in both subtypes of craniopharyngioma might therefore be an effective therapeutic strategy. FAU - Coy, Shannon AU - Coy S AD - Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts. AD - Harvard Medical School, Boston, Massachusetts. FAU - Rashid, Rumana AU - Rashid R AD - Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts. AD - Harvard Medical School, Boston, Massachusetts. FAU - Lin, Jia-Ren AU - Lin JR AD - Harvard Medical School, Boston, Massachusetts. AD - MS LINCS Center and Laboratory of Systems Pharmacology, Boston, Massachusetts. FAU - Du, Ziming AU - Du Z AD - Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts. FAU - Donson, Andrew M AU - Donson AM AD - Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado. AD - Morgan Adams Foundation Pediatric Brain Tumor Research Program, Denver, Colorado. FAU - Hankinson, Todd C AU - Hankinson TC AD - Morgan Adams Foundation Pediatric Brain Tumor Research Program, Denver, Colorado. AD - Department of Neurosurgery, Children's Hospital Colorado, Aurora, Colorado. FAU - Foreman, Nicholas K AU - Foreman NK AD - Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado. AD - Morgan Adams Foundation Pediatric Brain Tumor Research Program, Denver, Colorado. FAU - Manley, Peter E AU - Manley PE AD - Harvard Medical School, Boston, Massachusetts. AD - Pediatric Medical Neuro-Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts. FAU - Kieran, Mark W AU - Kieran MW AD - Harvard Medical School, Boston, Massachusetts. AD - Pediatric Medical Neuro-Oncology, Dana-Farber Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts. FAU - Reardon, David A AU - Reardon DA AD - Harvard Medical School, Boston, Massachusetts. AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. FAU - Sorger, Peter K AU - Sorger PK AD - Harvard Medical School, Boston, Massachusetts. AD - MS LINCS Center and Laboratory of Systems Pharmacology, Boston, Massachusetts. AD - Ludwig Center at Harvard, Boston, Massachusetts. FAU - Santagata, Sandro AU - Santagata S AD - Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts. AD - Harvard Medical School, Boston, Massachusetts. AD - MS LINCS Center and Laboratory of Systems Pharmacology, Boston, Massachusetts. AD - Ludwig Center at Harvard, Boston, Massachusetts. AD - Department of Pathology, Boston Children's Hospital, Boston, Massachusetts. AD - Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts. LA - eng GR - P50 GM107618/GM/NIGMS NIH HHS/United States GR - U54 HL127365/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - England TA - Neuro Oncol JT - Neuro-oncology JID - 100887420 RN - 0 (B7-H1 Antigen) RN - 0 (Biomarkers, Tumor) RN - 0 (CD274 protein, human) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) SB - IM MH - B7-H1 Antigen/*metabolism MH - Biomarkers, Tumor/*metabolism MH - Craniopharyngioma/classification/metabolism/*pathology MH - Fluorescent Antibody Technique MH - Follow-Up Studies MH - Humans MH - Neoplasm Recurrence, Local/metabolism/*pathology MH - Pituitary Neoplasms/classification/metabolism/*pathology MH - Prognosis MH - Programmed Cell Death 1 Receptor/*metabolism MH - Stromal Cells/*metabolism PMC - PMC6280314 EDAT- 2018/03/07 06:00 MHDA- 2019/10/02 06:00 PMCR- 2019/07/05 CRDT- 2018/03/07 06:00 PHST- 2018/03/07 06:00 [pubmed] PHST- 2019/10/02 06:00 [medline] PHST- 2018/03/07 06:00 [entrez] PHST- 2019/07/05 00:00 [pmc-release] AID - 4917565 [pii] AID - noy035 [pii] AID - 10.1093/neuonc/noy035 [doi] PST - ppublish SO - Neuro Oncol. 2018 Jul 5;20(8):1101-1112. doi: 10.1093/neuonc/noy035.