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Citrullinated glucose-regulated protein 78 is a candidate target for cancer immunotherapy

ABSTRACT: In this study we investigate the potential of targeting citrullinated GRP78 for cancer therapy. We select five peptides and show the identification CD4 T cell responses to one citrullinated GRP78 epitope that is restricted through HLA DP*0401 and HLA-DR*0101 alleles. This peptide is detected by mass spectrometry in B16 melanoma grown in vivo and citrulline specific CD4 responses to this epitope mediate efficient therapy of established B16 melanoma tumours in HHDII/DP4 transgenic mouse model. We demonstrate the existence of a repertoire of responses to the citrullinated GRP78 peptide in healthy individuals.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Skin

SUBMITTER: Michael Bremang

LAB HEAD: Victoria Brentville

PROVIDER: PXD037918 | Pride | 2022-11-29

REPOSITORIES: Pride

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Project description:Bronchopulmonary dysplasia (BPD), a chronic lung disease of prematurity, has been linked to endoplasmic reticulum (ER) stress. To investigate a causal role for ER stress in BPD pathogenesis, we generated mice (cGrp78f/f) with lung epithelial cell-specific knockout (KO) of Grp78, a gene encoding the ER chaperone 78-kDa glucose-regulated protein (GRP78), a master regulator of ER homeostasis and the unfolded protein response (UPR). Lung epithelial-specific Grp78 KO disrupted lung morphogenesis, causing developmental arrest, increased alveolar epithelial type II cell apoptosis and decreased surfactant protein and type I cell marker expression in perinatal lungs. cGrp78f/f pups died immediately after birth, likely due to respiratory distress. Importantly, Grp78 KO triggered UPR activation with marked induction of pro-apoptotic transcription factor C/EBP homologous protein (CHOP). Increased expression of genes involved in oxidative stress and cell death and decreased expression of genes encoding antioxidant enzymes suggest a role for oxidative stress in alveolar epithelial cell (AEC) apoptosis. Increased Smad3 phosphorylation and expression of transforming growth factor-Î² (TGF-Î²)/Smad3 targets Cdkn1a (encoding p21) and Gadd45a suggest that interactions among the apoptotic arm of the UPR, oxidative stress and TGF-Î²/Smad signaling pathways contribute to Grp78 KO-induced AEC apoptosis and developmental arrest. Chemical chaperone taursodeoxycholic acid reduced UPR activation and apoptosis in cGrp78f/f lungs cultured ex vivo, confirming a role for ER stress in observed AEC abnormalities. These results demonstrate a key role for GRP78 in AEC survival and gene expression during lung development through modulation of ER stress and suggest the UPR as a potential therapeutic target in BPD. Whole-genome expression profiling was performed using MouseRef-8 v2.0 Expression BeadChips (Illumina) on RNA isolated from lungs of four Grp78f/f and three cGrp78f/f mice at E18.

			Action	DRS
	21108-01.msf	Msf
	21108-01.raw	Raw
	21108-02.msf	Msf
	21108-02.raw	Raw
	21108-03.msf	Msf

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Citrullinated glucose-regulated protein 78 is a candidate target for cancer immunotherapy

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