Proteogenomic Analysis Unveils the HLA Class I-Presented Immunopeptidome in Melanoma and EGFR-Mutant Lung Adenocarcinoma

Qi, Yue; Maity, Tapan K.; Cultraro, Constance M.; Misra, Vikram; Zhang, Xu; Ade, Catherine M.; Gao, Shaojian; Milewski, David; Nguyen, Khoa Dang P.; Ebrahimabadi, Mohammad Haghir; Hanada, Ken‐ichi; Khan, Javed; Sahinalp, S. Cenk; Yang, James Chih‐Hsin; Guha, Udayan

doi:10.1016/j.mcpro.2021.100136

Cited by 20 publications

(17 citation statements)

References 89 publications

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“…Interestingly, MALAT1 was one of many lncRNAs that we found to encode an antigenic peptide, thus extending the significance of MALAT1 in cancer by connecting its lncRNA expression with a derived peptide and antigen presentation. Whilst we cannot currently comment on the potential immunogenicity of this MALAT1 derived peptide, other studies where bioinformatics approaches have been deployed suggested that tumour associated antigens can be derived from non-canonical parts of the genome although, to our knowledge, this concept remains to be proven [34][35][36][37][38] .…”

Section: Discussionmentioning

confidence: 93%

Long non-coding RNA-derived peptides are immunogenic and drive a potent anti-tumour response

Barczak

Carr

et al. 2023

Nat Commun

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Protein arginine methyltransferase (PRMT) 5 is over-expressed in a variety of cancers and the master transcription regulator E2F1 is an important methylation target. We have explored the role of PRMT5 and E2F1 in regulating the non-coding genome and report here a striking effect on long non-coding (lnc) RNA gene expression. Moreover, many MHC class I protein-associated peptides were derived from small open reading frames in the lncRNA genes. Pharmacological inhibition of PRMT5 or adjusting E2F1 levels qualitatively altered the repertoire of lncRNA-derived peptide antigens displayed by tumour cells. When presented to the immune system as either ex vivo-loaded dendritic cells or expressed from a viral vector, lncRNA-derived peptides drove a potent antigen-specific CD8 T lymphocyte response, which translated into a significant delay in tumour growth. Thus, lncRNA genes encode immunogenic peptides that can be deployed as a cancer vaccine.

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Section: Discussionmentioning

confidence: 93%

Long non-coding RNA-derived peptides are immunogenic and drive a potent anti-tumour response

Barczak

Carr

et al. 2023

Nat Commun

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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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“…Of these, long-non-coding RNAs (lncRNAs) are especially notable for their crucial role in modulating immune responses [ 15 , 16 ] and their ability to translate short peptides [ 17 ]. LncRNAs have also been reported to translate neoantigens that can be presented by major histocompatibility complex class 1 molecules (MHC I), which contributes to essential cellular immunosurveillance [ 17 ] and expands the range of immunopeptidomes that can be targeted for immunotherapy [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Scoring model based on the signature of non-m6A-related neoantigen-coding lncRNAs assists in immune microenvironment analysis and TCR-neoantigen pair selection in gliomas

Zhao

et al. 2022

J Transl Med

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Background Small peptides encoded by long non-coding RNAs (lncRNAs) have attracted attention for their various functions. Recent studies indicate that these small peptides participate in immune responses and antigen presentation. However, the significance of RNA modifications remains unclear. Methods Thirteen non-m6A-related neoantigen-coding lncRNAs were selected for analysis from the TransLnc database. Next, a neoantigen activation score (NAS) model was established based on the characteristics of the lncRNAs. Machine learning was employed to expand the model to two additional RNA-seq and two single-cell sequencing datasets for further validation. The DLpTCR algorithm was used to predict T cell receptor (TCR)-peptide binding probability. Results The non-m6A-related NAS model predicted patients’ overall survival outcomes more precisely than the m6A-related NAS model. Furthermore, the non-m6A-related NAS was positively correlated with tumor cells’ evolutionary level, immune infiltration, and antigen presentation. However, high NAS gliomas also showed more PD-L1 expression and high mutation frequencies of T-cell positive regulators. Interestingly, results of intercellular communication analysis suggest that T cell-high neoplastic cell interaction is weaker in both of the NAS groups which might arise from decreased IFNGR1 expression. Moreover, we identified unique TCR-peptide pairs present in all glioma samples based on peptides encoded by the 13 selected lncRNAs. And increased levels of neoantigen-active TCR patterns were found in high NAS gliomas. Conclusions Our work suggests that non-m6A-related neoantigen-coding lncRNAs play an essential role in glioma progression and that screened TCR clonotypes might provide potential avenues for chimeric antigen receptor T cell (CAR-T) therapy for gliomas.

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Proteogenomic Analysis Unveils the HLA Class I-Presented Immunopeptidome in Melanoma and EGFR-Mutant Lung Adenocarcinoma

Cited by 20 publications

References 89 publications

Long non-coding RNA-derived peptides are immunogenic and drive a potent anti-tumour response

Long non-coding RNA-derived peptides are immunogenic and drive a potent anti-tumour response

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

Scoring model based on the signature of non-m6A-related neoantigen-coding lncRNAs assists in immune microenvironment analysis and TCR-neoantigen pair selection in gliomas

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