Immunopeptidomic Analyses of Colorectal Cancers With and Without Microsatellite Instability

Cleyle, Jenna; Hardy, Marie-Pierre; Minati, Robin; Courcelles, Mathieu; Durette, Chantal; Lanoix, Joël; Laverdure, Jean‐Philippe; Vincent, Krystel; Perreault, Claude; Thibault, Pierre

doi:10.1016/j.mcpro.2022.100228

Cited by 26 publications

(27 citation statements)

References 86 publications

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“…The proteogenomics pipeline we used, Peptide-PRISM, is independent of RNA-seq and Ribo-seq but enables the detection of HLA-I ligands potentially originating from any region of the genome, including CDS, UTR, off-frame, ncRNA, intronic and intergenic regions (Figure 1A). Like previous immunopeptidomics studies (20–24,31,33,34,39), we observed that nonC HLA-I ligands were frequently detected across different cancer types (Figure 1B). Because we were interested in tumor-specific candidates we used healthy immunopeptidome data to exclude peptides derived from ORFs present in non-malignant cells.…”

Section: Discussionsupporting

confidence: 88%

Immunogenicity of non-canonical HLA-I tumor ligands identified through proteogenomics

Lozano-Rabella

Garcia-Garijo

Palomero

et al. 2022

Preprint

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Tumor antigens are central to antitumor immunity. Recent evidence suggests that peptides from non-canonical (nonC) aberrantly translated proteins can be presented on HLA-I by tumor cells. Here, we investigated the immunogenicity of nonC tumor HLA-I ligands (nonC-TL) to better understand their contribution to cancer immunosurveillance and their therapeutic applicability. Using proteogenomics, we identified 517 nonC-TL from 9 patients with melanoma, gynecological, and head and neck cancer. We found no recognition of the 507 nonC-TL tested by autologous ex vivo expanded tumor reactive T-cell cultures while the same cultures demonstrated reactivity to mutated, cancer-germline, or melanocyte differentiation antigens. However, in vitro sensitization of donor peripheral blood lymphocytes against 170 selected nonC-TL, led to the identification of T-cell receptors (TCRs) specific to three nonC-TL, two of which mapped to the UTR5 regions of HOXC13 and ZKSCAN1, and one mapping to a non-coding spliced variant of C5orf22C. T cells targeting these nonC-TL recognized cancer cell lines naturally presenting their corresponding antigens. Expression of the three immunogenic nonC-TL was shared across tumor types and barely or not detected in normal cells. Our findings predict a limited contribution of nonC-TL to cancer immunosurveillance but demonstrate they may be attractive novel targets for widely applicable immunotherapies.

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Section: Discussionsupporting

confidence: 88%

Immunogenicity of non-canonical HLA-I tumor ligands identified through proteogenomics

Lozano-Rabella

Garcia-Garijo

Palomero

et al. 2022

Preprint

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“…Many of such peptides were from genes involved in colorectal cancer progression. Future vaccine research could use such findings to develop T-cell-based vaccines, in which T cells are primed against these antigens to target and destroy these tumors [43] .…”

Section: Cancer Vaccines: From Biological Mechanisms To Engineeringmentioning

confidence: 99%

Therapeutic cancer vaccines: From biological mechanisms and engineering to ongoing clinical trials

Sobhani

Scaggiante

Morris

et al. 2022

Cancer Treatment Reviews

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“…The emerging field of proteogenomics has been successfully applied to identify unique HLA-associated mutant peptides in cancer, characterizing HLA-presented epitopes that are expressed specifically by various tumors types (9)(10)(11)(12). Previous work on identifying HBV-HLA epitopes in HCC has been performed, identifying several HBV peptides (13,14).…”

Section: Introductionmentioning

confidence: 99%

Proteogenomic identification of Hepatitis B virus (HBV) genotype-specific HLA-I restricted peptides from HBV-positive patient liver tissues

et al. 2022

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The presentation of virus-derived peptides by HLA class I molecules on the surface of an infected cell and the recognition of these HLA-peptide complexes by, and subsequent activation of, CD8+ cytotoxic T cells provides an important mechanism for immune protection against viruses. Recent advances in proteogenomics have allowed researchers to discover a growing number of unique HLA-restricted viral peptides, resulting in a rapidly expanding repertoire of targets for immunotherapeutics (i.e. bispecific antibodies, engineered T-cell receptors (TCRs), chimeric antigen receptor T-cells (CAR-Ts)) to infected tissues. However, genomic variability between viral strains, such as Hepatitis-B virus (HBV), in combination with differences in patient HLA alleles, make it difficult to develop therapeutics against these targets. To address this challenge, we developed a novel proteogenomics approach for generating patient-specific databases that enable the identification of viral peptides based on the viral transcriptomes sequenced from individual patient liver samples. We also utilized DNA sequencing of patient samples to identify HLA genotypes and assist in target selection. Liver samples from 48 HBV infected patients, primarily from Asia, were examined to reconstruct patient-specific HBV genomes, identify regions within the human chromosomes targeted by HBV integrations and obtain a comprehensive view of HBV peptide epitopes using our HLA class-I (HLA-I) immunopeptidomics discovery platform. Two previously reported HLA associated HBV-derived peptides, HLA-A02 binder FLLTRILTI (S194-202) from the large surface antigen and HLA-A11 binder STLPETTVVRR (C141-151) from the capsid protein were validated by our discovery platform, but both were detected at very low frequencies. In addition, we identified and validated, using heavy peptide analogues, novel strain-specific HBV-HLA associated peptides, such as GSLPQEHIVQK (P606-616) and variants. Overall, our novel approach can guide the development of bispecific antibody, TCR-T, or CAR-T based therapeutics for the treatment of HBV-related HCC and inform vaccine development.

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Immunopeptidomic Analyses of Colorectal Cancers With and Without Microsatellite Instability

Cited by 26 publications

References 86 publications

Immunogenicity of non-canonical HLA-I tumor ligands identified through proteogenomics

Immunogenicity of non-canonical HLA-I tumor ligands identified through proteogenomics

Therapeutic cancer vaccines: From biological mechanisms and engineering to ongoing clinical trials

Proteogenomic identification of Hepatitis B virus (HBV) genotype-specific HLA-I restricted peptides from HBV-positive patient liver tissues

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