Dataset Information

Discovery of tumor-specific antigens in colorectal cancer

ABSTRACT: Colorectal cancer is the second leading cause of cancer death worldwide, and the incidence of this disease is expected to increase as global socioeconomic changes occur. Immune checkpoint inhibition therapy is effective in treating a minority of colorectal cancer tumors; however, microsatellite stable tumors do not respond well to this treatment. Emerging cancer immunotherapeutic strategies aim to activate a cytotoxic T cell response against tumor-specific antigens, presented exclusively at the cell surface of cancer cells. These antigens are rare and are most effectively identified with a mass spectrometry-based approach, which allows the direct sampling and sequencing of these peptides. While the few tumor-specific antigens identified to date derived from coding regions of the genome, recent findings indicate that a large proportion of tumor-specific antigens originate from allegedly noncoding regions. Here, we employed a novel proteogenomic approach to identify tumor antigens in a collection of colorectal cancer-derived cell lines and biopsy samples consisting of matched tumor and normal adjacent tissue. The generation of personalized cancer databases paired with mass spectrometry analyses permitted the identification of more than 30 000 unique MHC I-associated peptides. We identified 19 putative tumor-specific antigens in both microsatellite stable and unstable tumors, over two-thirds of which were derived from non-coding regions. Many of these peptides were derived from source genes known to be involved in colorectal cancer progression, suggesting that antigens from these genes could have therapeutic potential in a wide range of tumors. These findings could benefit the development of T cell-based vaccines, in which T cells are primed against these antigens to target and eradicate tumors. Such a vaccine could be used in tandem with existing immune checkpoint inhibition therapies, to bridge the gap in treatment efficacy across subtypes of colorectal cancer with varying prognoses.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Colon

DISEASE(S): Colon Adenocarcinoma

SUBMITTER: Courcelles Mathieu

LAB HEAD: Pierre Thibault

PROVIDER: PXD028309 | Pride | 2022-04-13

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	1_0_0_3__PP486_uploaded_file_id_905.fasta	Fasta
	2_0_0_3__PP487_uploaded_file_id_907.fasta	Fasta
	3_0_0_3__PP488_uploaded_file_id_909.fasta	Fasta
	CRC_026019T_TMT_200720_1.mgf	Mgf
	CRC_026019T_TMT_200720_1.raw	Raw

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Publications

Immunopeptidomic analyses of colorectal cancers with and without microsatellite instability.

Cleyle Jenna J Hardy Marie-Pierre MP Minati Robin R Courcelles Mathieu M Durette Chantal C Lanoix Joel J Laverdure Jean-Philippe JP Vincent Krystel K Perreault Claude C Thibault Pierre P

Molecular & cellular proteomics : MCP 20220401 5

Colorectal cancer is the second leading cause of cancer death worldwide, and the incidence of this disease is expected to increase as global socioeconomic changes occur. Immune checkpoint inhibition therapy is effective in treating a minority of colorectal cancer tumors; however, microsatellite stable tumors do not respond well to this treatment. Emerging cancer immunotherapeutic strategies aim to activate a cytotoxic T cell response against tumor-specific antigens, presented exclusively at the ...[more]

PMID: 35367648

Similar Datasets

Project description:Colorectal cancer is the second leading cause of cancer death worldwide, and the incidence of this disease is expected to increase as global socioeconomic changes occur. Immune checkpoint inhibition therapy is effective in treating a minority of colorectal cancer tumors; however, microsatellite stable tumors do not respond well to this treatment. Emerging cancer immunotherapeutic strategies aim to activate a cytotoxic T cell response against tumor-specific antigens, presented exclusively at the cell surface of cancer cells. These antigens are rare and are most effectively identified with a mass spectrometry-based approach, which allows the direct sampling and sequencing of these peptides. While the few tumor-specific antigens identified to date are derived from coding regions of the genome, recent findings indicate that a large proportion of tumor-specific antigens originate from allegedly noncoding regions. Here, we employed a novel proteogenomic approach to identify tumor antigens in a collection of colorectal cancer-derived cell lines and biopsy samples consisting of matched tumor and normal adjacent tissue. The generation of personalized cancer databases paired with mass spectrometry analyses permitted the identification of more than 30 000 unique MHC I-associated peptides. We identified 19 tumor-specific antigens in both microsatellite stable and unstable tumors, over two-thirds of which were derived from non-coding regions. Many of these peptides were derived from source genes known to be involved in colorectal cancer progression, suggesting that antigens from these genes could have therapeutic potential in a wide range of tumors. These findings could benefit the development of T cell-based vaccines, in which T cells are primed against these antigens to target and eradicate tumors. Such a vaccine could be used in tandem with existing immune checkpoint inhibition therapies, to bridge the gap in treatment efficacy across subtypes of colorectal cancer with varying prognoses. Data are available via ProteomeXchange with identifier PXD028309.

Project description:Colorectal cancer (CRC) is still one of the most common causes of cancer-related death worldwide (World Health Organization, Fact sheet NM-BM-0297, October 2011). Though, therapeutic options improved over the past years, the prognosis of metastatic colorectal cancer (mCRC) remains poor with a median survival of 18-21 months. Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR) are used for the palliative treatment of metastatic colorectal cancer (mCRC) carrying a KRAS-wildtype. Among the tumors with a KRAS-wildtype, only 35% respond, and alterations of other signaling molecules and pathways modulate therapeutic response. In this study we analyzed the effect of KRAS-mutations on intracellular signaling cascades to find new therapeutic approaches for patients with mCRC. Reverse-phase protein array and gene array technology was applied to sixteen adenocarcinomas of the sigmoid colon carrying either wildtype (n=8) or mutant (n=8) KRAS. Differential expression was validated on 49 sigmoid cancers by RT-PCR, Western blot and immunohistochemistry. In a screening for members of signaling pathways known to have a high impact on tumor development in colon cancer, we found 14 proteins downregulated in tumors with mutated KRAS. Subsequently, we compared the data of the protein arrays with the results of gene expression arrays performed with the same samples. We confirmed the differential expression of eight genes as a function of the KRAS genotype of the tumor. To further validate the differential expression of these candidates, we performed quantitative expression analysis and immunohistochemical staining of an independent validation series comprising 49 CRC patient samples. It was clearly demonstrated that the expression of EGFR is decreased in colorectal carcinomas with a mutant KRAS genotype. mRNA was obtained from 16 patients with colorectal cancer (8 with and 8 without KRAS-mutation). mRNA was extracted from neoplastic and non-neoplastic colon mucosa and analyzed separately by Affymetrix Human Gene 1.1 ST GeneChips finally generating 32 separate data sets.