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LC-MSMS of the MHC-I immunopeptidome of human melanoma

ABSTRACT: While immune checkpoint blockade (ICB) therapy has significantly improved the outcome of metastatic melanoma and non-small cell lung cancer (NSCLC), most patients do not derive long-term benefits. Previous studies suggest that treatment failure is partly due to insufficient immune recognition of tumor antigens (TAs). Notably, immune targeting of TAs has focused on TAs derived from non-synonymous genomic mutations. We used a proteogenomic approach combining RNA-sequencing and mass spectrometry to study the MHC I-immunopeptidome of cutaneous melanoma and NSCLC samples. The RNA-sequencing of each sample was used to construct sample-specific databases for the mass spectrometry-based identification of MHC I-associated peptides (MAPs). MAPs were then filtered based on their RNA expression in the respective cancer types from The Cancer Genome Atlas (TCGA-SKCM for melanoma MAPs, or TCGA-LUSC and TCGA-LUAD for NSCLC MAPs) vs. benign tissues (from the Genotype-Tissue Expression (GTEx) Project, medullary thymic epithelial cells, purified blood and bone marrow cells, and normal melanocytes for melanoma or bronchial brushing samples for NSCLC). MAPs were classified as mutated tumor-specific antigens (mTSAs, derived from non-synonymous mutations expressed in the sample of origin), or unmutated tumor antigens: aberrantly expressed tumor-specific antigens (aeTSAs, no/low expression in benign tissues and at least two times higher expression in TCGA), tumor-associated antigens (TAAs, significant expression in benign tissues and at least two times higher expression in TCGA), lineage-associated antigens (LSAs, specific expression to cancer and normal tissue of origin, i.e., lung and bronchial brushing samples for NSCLC or skin and melanocytes for melanoma). The tumor antigens described here represent attractive targets for immunotherapy of melanoma and NSCLC.

INSTRUMENT(S): orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Melanocyte, Skin

DISEASE(S): Melanoma

SUBMITTER: Courcelles Mathieu

LAB HEAD: Pierre Thibault

PROVIDER: PXD043059 | Pride | 2025-02-19

REPOSITORIES: pride

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			Action	DRS
	0D5PCTRL_1_mtechuman_2__PP654_uploaded_file_id_1370.fasta	Fasta
	0D5PCTRL_contigs_20230117_0D5PCTRL_1_mtechuman_2__PP654__JJ_uploaded_file_id_1738.fasta	Fasta
	0D5P_Melanoma_ctrl__kmer_Comet_20170913_QEh1_LC1_CHC_SA_HLAIp_OD5P_ctrl_1_R1-comet.txt	Txt
	0D5P_Melanoma_ctrl__kmer_Comet_20170913_QEh1_LC1_CHC_SA_HLAIp_OD5P_ctrl_1_R2-comet.txt	Txt
	0D5P_Melanoma_ctrl__kmer_Comet_20170913_QEh1_LC1_CHC_SA_HLAIp_OD5P_ctrl_2_R1-comet.txt	Txt

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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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LC-MSMS of the MHC-I immunopeptidome of human melanoma

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