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Immunogenic noncoding cryptic peptides dominate the antigenic landscape of ovarian cancer

ABSTRACT: Increased infiltration of CD3+ and CD8+ T cells into ovarian cancer (OC) tumors is linked to better prognosis, but the specific antigens involved are unclear. Recent data suggests that HLA-I can present peptides from noncoding genomic regions, known as noncanonical or cryptic peptides, but their immunogenicity is underexplored. To address this, we used immunopeptidomic analysis and RNA sequencing on five metastatic OC tumors, identifying around 311 cryptic peptides total, with 40 to 83 per patient. Over 90% of these were novel, with only 9 matching existing datasets. Despite comprising less than 1% of total peptides, noncoding cryptic peptides were more abundant than other antigen types in OC samples. Notably, about 70% of the prioritized cryptic peptides elicited T cell activation, indicated by increased 4-1BB and IFNγ expression in autologous CD8+ T cells. This study reveals noncoding cryptic peptides as a significant class of immunogenic antigens in OC.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Ovary

DISEASE(S): Malignant Neoplasm Of Ovary

SUBMITTER: Akhilesh Pandey

LAB HEAD: Akhilesh Pandey

PROVIDER: PXD055609 | Pride | 2025-01-14

REPOSITORIES: pride

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Dataset's files

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			Action	DRS
	T1-6472_Ovarian_MHC_ClassI_082020.raw	Raw
	T1-6472_Ovarian_MHC_ClassI_082020_RNAseq_Noncoding.pdResult	Other
	T1-6472_Ovarian_MSFragger_MHC_ClassI_082020.pepXML	Pepxml
	T2-5327_Ovarian_MHC_ClassI_040921_RNAseq_Noncoding.pdResult	Other
	T2-5327_Ovarian_MHC_ClassI_091120.raw	Raw

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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.

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Immunogenic noncoding cryptic peptides dominate the antigenic landscape of ovarian cancer

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