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Multiplexed immunofluorescence reveals potential PD-1/PD-L1 pathway vulnerabilities in craniopharyngioma.

ABSTRACT: 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.

SUBMITTER: Coy S

PROVIDER: S-EPMC6280314 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Multiplexed immunofluorescence reveals potential PD-1/PD-L1 pathway vulnerabilities in craniopharyngioma.

Coy Shannon S Rashid Rumana R Lin Jia-Ren JR Du Ziming Z Donson Andrew M AM Hankinson Todd C TC Foreman Nicholas K NK Manley Peter E PE Kieran Mark W MW Reardon David A DA Sorger Peter K PK Santagata Sandro S

Neuro-oncology 20180701 8

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 dea ...[more]

PMID: 29509940

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Project description:Chagas disease (CD) is a neglected chronic infection caused by the protozoan parasite Trypanosoma cruzi (T. cruzi). A significant portion of infected people develops cardiac or digestive alterations over a lifetime. Since several chronic infections associated with antigen persistence and inflammation have been shown to lead to T cell exhaustion, new therapies targeting co-inhibitory receptors to regain T cell activity are under consideration. This study explored immune therapeutic approaches targeting the inhibitory PD-1/PD-L pathway in an experimental model for CD. Infected PD-L1 knockout mice (PD-L1 KO) showed increased systemic parasitemia in blood although no significant differences in parasite load were observed in different organs. Furthermore, we found no significant differences in the frequency of activated T cells or proinflammatory cytokine production when compared to WT counterparts. PD-L1 deficiency led to the production of IL-10 by CD8+ T cells and an upregulation of Tim-3 and CD244 (2B4). Unexpectedly, the lack of PD-L1 did not contribute to a significantly improved T cell response to infection. Single blockade and combined blockade of PD-1 and Tim-3 using monoclonal antibodies confirmed the results observed in infected. PD-L1 KO mice. Our results describe for the first time that the interruption of the PD-1/PD-L1 axis during acute T. cruzi infection does not necessarily enhance the immune response against this parasite. Its interruption favors increased levels of parasitemia and sustained upregulation of other co-inhibitory receptors as well as the production of regulatory cytokines. These results suggest that the clinical application of immune therapeutic approaches targeting the PD-1/PD-L1 axis in CD might be risky and associated with adverse events. It highlights that more research is urgently needed to better understand the immune regulation of T cells in CD before designing immune therapeutic approaches for a clinical context.

Dataset Information

Multiplexed immunofluorescence reveals potential PD-1/PD-L1 pathway vulnerabilities in craniopharyngioma.

Publications

Multiplexed immunofluorescence reveals potential PD-1/PD-L1 pathway vulnerabilities in craniopharyngioma.

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