Dataset Information

Tumor Apolipoprotein E is a key checkpoint blocking anti-tumor immunity in mouse melanoma.

ABSTRACT: Immunotherapy is a key modality in the treatment of cancer, but many tumors remain immune resistant. The classic mouse model of B16-F10 melanoma is immune resistant even in the face of checkpoint inhibition. Apolipoprotein E (apoE), a known immune suppressant is strikingly elevated in many human tumors, but its role in cancer immunology is not defined. We investigated the role of apoE in the immune micro-environment using a mouse melanoma model. We demonstrate that ApoE is -highly expressed in wild-type B16-F10 melanoma and serum levels progressively increase as tumors grow. The conditioned media from wild type ApoE secreting melanoma cells suppress T-cell activation in vitro while this suppressive effect is absent in conditioned media from ApoE knock out tumor cells. Mechanistically, apoE induces IL-10 secreting dendritic cells and stimulates T-cell apoptosis and arrest partially via the lrp8 receptor. Ablating ApoE in mice inoculated with tumor cells enabled tumor cell rejection and was associated with induction of immune pathway activation and immune cell infiltration. Tumor secreted apoE appears to be a potent immune cell checkpoint and targeting apoE is associated with enhanced tumor immunity in the mouse melanoma model.

SUBMITTER: Wu X

PROVIDER: S-EPMC9626815 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Tumor Apolipoprotein E is a key checkpoint blocking anti-tumor immunity in mouse melanoma.

Wu Xiaofang X Srinivasan Priya P Basu Mousumi M Zhang Peng P Saruwatari Michele M Thommandru Bernice B Jacobi Ashley A Behlke Mark M Sandler Anthony A

Frontiers in immunology 20221019

Immunotherapy is a key modality in the treatment of cancer, but many tumors remain immune resistant. The classic mouse model of B16-F10 melanoma is immune resistant even in the face of checkpoint inhibition. Apolipoprotein E (apoE), a known immune suppressant is strikingly elevated in many human tumors, but its role in cancer immunology is not defined. We investigated the role of apoE in the immune micro-environment using a mouse melanoma model. We demonstrate that ApoE is -highly expressed in w ...[more]

PMID: 36341364

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Project description:BackgroundTumor regression following immune checkpoint blockade (ICB) is often associated with immune-related adverse events (irAEs), marked by inflammation in non-cancerous tissues. This study was undertaken to investigate the functional relationship between anti-tumor and anti-self immunity, to facilitate irAE management while promoting anti-tumor immunity.MethodsMultiple biopsies from tumor and inflamed tissues were collected from a patient with melanoma experiencing both tumor regression and irAEs on ICB, who underwent rapid autopsy. Immune cells infiltrating melanoma lesions and inflamed normal tissues were subjected to gene expression profiling with multiplex qRT-PCR for 122 candidate genes. Subsequently, immunohistochemistry was conducted to assess the expression of 14 candidate markers of immune cell subsets and checkpoints. TCR-beta sequencing was used to explore T cell clonal repertoires across specimens.ResultsWhile genes involved in MHC I/II antigen presentation, IFN signaling, innate immunity and immunosuppression were abundantly expressed across specimens, irAE tissues over-expressed certain genes associated with immunosuppression (CSF1R, IL10RA, IL27/EBI3, FOXP3, KLRG1, SOCS1, TGFB1), including those in the COX-2/PGE2 pathway (IL1B, PTGER1/EP1 and PTGER4/EP4). Immunohistochemistry revealed similar proportions of immunosuppressive cell subsets and checkpoint molecules across samples. TCRseq did not indicate common TCR repertoires across tumor and inflammation sites, arguing against shared antigen recognition between anti-tumor and anti-self immunity in this patient.ConclusionsThis comprehensive study of a single patient with melanoma experiencing both tumor regression and irAEs on ICB explores the immune landscape across these tissues, revealing similarities between anti-tumor and anti-self immunity. Further, it highlights expression of the COX-2/PGE2 pathway, which is known to be immunosuppressive and potentially mediates ICB resistance. Ongoing clinical trials of COX-2/PGE2 pathway inhibitors targeting the major COX-2 inducer IL-1B, COX-2 itself, or the PGE2 receptors EP2 and EP4 present new opportunities to promote anti-tumor activity, but may also have the potential to enhance the severity of ICB-induced irAEs.

Dataset Information

Tumor Apolipoprotein E is a key checkpoint blocking anti-tumor immunity in mouse melanoma.

Publications

Tumor Apolipoprotein E is a key checkpoint blocking anti-tumor immunity in mouse melanoma.

Similar Datasets

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