Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing

@article{Yadav2014PredictingIT,
  title={Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing},
  author={Mahesh Yadav and Suchit Jhunjhunwala and Qui T. Phung and Patrick J. Lupardus and Josh Tanguay and Stephanie M Bumbaca and Christian Franci and Tommy K. Cheung and Jens Fritsche and Toni Weinschenk and Zora Modru{\vs}an and Ira Mellman and Jennie R. Lill and L{\'e}lia Delamarre},
  journal={Nature},
  year={2014},
  volume={515},
  pages={572-576}
}
Human tumours typically harbour a remarkable number of somatic mutations. If presented on major histocompatibility complex class I molecules (MHCI), peptides containing these mutations could potentially be immunogenic as they should be recognized as ‘non-self’ neo-antigens by the adaptive immune system. Recent work has confirmed that mutant peptides can serve as T-cell epitopes. However, few mutant epitopes have been described because their discovery required the laborious screening of patient… 

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References

SHOWING 1-10 OF 38 REFERENCES

Exploiting the mutanome for tumor vaccination.

The findings provide a comprehensive picture of the mutanome of B16F10 melanoma and offer insight into the extent of the immunogenicity of nonsynonymous base substitution mutations, and argue that the use of deep sequencing to systematically analyze immunogenic mutations may pave the way for individualized immunotherapy of cancer patients.

Cancer Exome Analysis Reveals a T Cell Dependent Mechanism of Cancer Immunoediting

It is demonstrated that the strong immunogenicity of an unedited tumour can be ascribed to expression of highly antigenic mutant proteins and shown that outgrowth of tumour cells that lack these strong antigens via a T-cell-dependent immunoselection process represents one mechanism of cancer immunoediting.

The MHC class I peptide repertoire is molded by the transcriptome

A novel high-throughput mass spectrometry approach is developed that yields an accurate definition of the nature and relative abundance of unlabeled peptides presented by MHC I molecules and yields unique insights into the genesis of the MIP repertoire in normal and neoplastic cells.

MHC I-associated peptides preferentially derive from transcripts bearing miRNA response elements.

The data support an emerging model in which the generation of MIPs by a transcript depends on its abundance and DRiP rate, which is regulated to a large extent by miRNAs.

Expression of tumour-specific antigens underlies cancer immunoediting

It is shown that recognition of tumour-specific antigens by lymphocytes is critical for immunoediting against sarcomas, and primary Sarcomas were edited to become less immunogenic through the selective outgrowth of cells that were able to escape T lymphocyte attack.

Mutational heterogeneity in cancer and the search for new cancer genes

A fundamental problem with cancer genome studies is described: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds and the list includes many implausible genes, suggesting extensive false-positive findings that overshadow true driver events.

Surveillance of the Tumor Mutanome by T Cells during Progression from Primary to Recurrent Ovarian Cancer

The findings reveal the limitations of spontaneous tumor immunity in the setting of standard treatments and suggest a high degree of ignorance of tumor mutations that could potentially be reversed by immunotherapy.

PD-1 identifies the patient-specific CD8⁺ tumor-reactive repertoire infiltrating human tumors.

It is demonstrated that PD-1 expression on CD8⁺ TILs also accurately identifies the repertoire of clonally expanded tumor-reactive cells and reveal a dual importance of PD- 1 expression in the tumor microenvironment.

Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer

SPOP mutations may define a new molecular subtype of prostate cancer, with mutations involving the SPOP substrate-binding cleft in 6–15% of tumors across multiple independent cohorts.

The relationship between class I binding affinity and immunogenicity of potential cytotoxic T cell epitopes.

The data suggest that holes in the functional T cell repertoire, if they exist, may be relatively rare and correlate well with class I binding affinity measurements of either naturally processed peptides or previously described T cell epitopes.