Dataset Information

Reshaping of the MHC-I ligandome in response to reovirus-based cancer immunotherapy

ABSTRACT: Oncolytic viruses (OVs), known for their cancer-killing characteristics, overturn tumor-associated defects in antigen presentation through the MHC class I pathway and induce protective neo antitumor CD8 T cell responses. Nonetheless, whether OVs shape the tumor MHC-I ligandome remains unknown. Here, we investigated if an OV induces the presentation of novel MHC I-bound tumor antigens (termed tumor MHC-I ligands). Using comparative mass spectrometry (MS)-based MHC-I ligandomics, we determined differential tumor MHC-I ligand expression following treatment with oncolytic reovirus in a murine ovarian cancer model. In vitro we found that reovirus induces the presentation of tumor MHC-I ligands in cancer cells. Concurrent multiplexed quantitative proteomics revealed that the changes in tumor MHC-I ligand presentation were mostly independent of reovirus-induced alterations of their source proteins. In an in vivo model, tumor MHC-I ligands were induced by reovirus in tumors but also, more importantly, analysis of spleens (a source of antigen-presenting cells) showed exclusive induction of most MHC-I ligands occurred in tumor-bearing mice. Finally, IFNγ assays demonstrated immunogenicity of the reovirus-induced MHC-I ligands. OV-induced MHC-I responses may be exploited in combinatorial approaches to promote the efficacy of cancer immunotherapies.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Malignant Neoplasm Of Ovary

SUBMITTER: Patrick Murphy

LAB HEAD: Shashi Gujar

PROVIDER: PXD013066 | Pride | 2019-05-20

REPOSITORIES: Pride

ACCESS DATA

Publications

Therapy-Induced MHC I Ligands Shape Neo-Antitumor CD8 T Cell Responses during Oncolytic Virus-Based Cancer Immunotherapy.

Murphy J Patrick JP Kim Youra Y Clements Derek R DR Konda Prathyusha P Schuster Heiko H Kowalewski Daniel J DJ Paulo Joao A JA Cohen Alejandro M AM Stevanovic Stefan S Gygi Steven P SP Gujar Shashi S

Journal of proteome research 20190529 6

Oncolytic viruses (OVs), known for their cancer-killing characteristics, also overturn tumor-associated defects in antigen presentation through the MHC class I pathway and induce protective neo-antitumor CD8 T cell responses. Nonetheless, whether OVs shape the tumor MHC-I ligandome remains unknown. Here, we investigated if an OV induces the presentation of novel MHC I-bound tumor antigens (termed tumor MHC-I ligands). Using comparative mass spectrometry (MS)-based MHC-I ligandomics, we determine ...[more]

PMID: 31095916

Similar Datasets

Project description:Immune evasion is an important hallmark of cancer ensured by diverse strategies, including immunosuppression and downregulation of antigen presentation. Here, to restore immunogenicity of cancer cells, we employed the minimal gene regulatory network of highly immunogenic type 1 conventional dendritic cells (cDC1) to reprogram cancer cells into professional antigen presenting cells (APCs). We showed that enforced expression of PU.1, IRF8 and BATF3 (PIB) was sufficient to induce cDC1 phenotype in 33 cell lines derived from human and mouse hematological and solid tumors. PIB gradually modified the cancer cell transcriptional and epigenetic program imposing global antigen presentation and cDC1 gene signatures within 9 days. cDC1 reprogramming restored the expression of antigen presentation complexes as well as co-stimulatory molecules at the cell surface, leading to the presentation of endogenous antigens on MHC-I, and to CD8+ T cell mediated killing. Functionally, tumor- APCs acquired the ability to uptake and process exogenous proteins and dead cells, secreted inflammatory cytokines and cross-presented antigens to naïve CD8+ T cells. Importantly, tumor-APCs were efficiently generated at the single cell level from primary cancer cells of 7 solid tumors that presented antigens to memory and naïve T-cells, as well as to activated patient-specific intra-tumoral lymphocytes. Alongside antigen presentation, tumor-APCs harboring TP53, KRAS and PTEN mutations showed impaired tumorigenicity in vitro and in vivo. Finally, using in vivo mouse models of melanoma, we showed that intra-tumoral injection of tumor-APCs promoted lymphoid infiltration, delayed tumor growth and increased survival. The anti-tumor immunity elicited by tumor-APCs was synergistic with immune checkpoint inhibitors enabling tumor eradication. Our approach combines cDC1’s antigen processing and presenting abilities with endogenous generation of tumor antigens and serves as a platform for the development of novel immunotherapies based on endowed antigen presentation in cancer cells.

Dataset Information

Reshaping of the MHC-I ligandome in response to reovirus-based cancer immunotherapy

Publications

Therapy-Induced MHC I Ligands Shape Neo-Antitumor CD8 T Cell Responses during Oncolytic Virus-Based Cancer Immunotherapy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure