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MUTAEDITING Report Summary

Project ID: 339842
Funded under: FP7-IDEAS-ERC
Country: Germany

Mid-Term Report Summary - MUTAEDITING (Mutation-driven immunoediting of human cancer?)

Stand alone description
The basic hypothesis of MUTAEDITING was that the spectrum of mutations found in an established tumor of a patient should be diminished by preceding immune reactions that had eliminated tumor cells presenting immunogenic mutated peptides. During the first half of the project time it turned out that the basis of this hypothesis -- that the number of HLA-presented mutated peptides is diminished -- was utterly correct: we could not find a single one. Thus, it is very likely that the reason for this is indeed negative immune selection, although we could not prove this so far in the absence of identified mutated peptides.
At this point, it is important to note that the tumor entities we analyzed were those with intermediate mutation load, with 20 to 200 validated exome mutations per tumor. Other groups have recently reported mutated HLA ligands in melanoma. In one report, tumors with over 1000 validated exome mutations had between zero and eight mutated peptides as detectable by mass spectrometry.
Thus, taken together our own work with recently published reports, we conclude that the frequency of exome mutations giving rise to HLA presented mutated peptides is lower than 1 percent.
Our extended hypothesis was: “T- cell responses against HLA-presented peptides representing mutations or other genetic, epigenetic, or proteomic alterations of cancer cells are a selective force throughout cancer evolution in a patient”.
Thus, in parallel to the search for mutated peptides we analyzed the entire HLA ligandome of more than 100 tumor/normal tissue pairs to search for such other alterations. Indeed, we could detect massivley altered ligandome expression in every single tumor sample analyzed, including metabolomic changes. Such tumor specific ligands could be useful for cancer immunotherapy.
In the next half of the project time, we will 1) continue to search for mutated HLA ligands in tumors with higher mutation load (melanoma, lung carcinomas), 2) search for the reasons of altered HLA ligandome expression in tumors, and their influence on immune recognition by patient’s T cells.
Interestingly, we recently found that a tumor mutation in a signal pathway molecule can lead to increased expression of non-mutated HLA ligands from molecules downstream in that signalling pathway. Thus, we will follow this new aspect in the future. In addition, we will further concentrate on the other genetic, epigenetic, or proteomic alterations from our original extended hypothesis.
The surprising finding that the frequency of exome mutations giving rise to HLA presented mutated peptides and detectable by mass spetrometry is lower than 1 percent will have important consequences on present and future attempts in immunotherapy of cancer.

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