Final Report Summary - MUTAEDITING (Mutation-driven immunoediting of human cancer?)
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 in the first half. We then found a few in the recent 2 years. It is very likely that the reason for this is indeed negative immune selection, although we could not prove this formally. However, a number of reports from others also point in this direction.
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. These relations have now been carefully analyzed and interpreted in our recent publication in Genome Medicine (2019). Accordingly, far less than 1% of all somatic variants in a cancer will lead to HLA-presented neoantigens. These relevation is surprising for the majority in this field, and will lead to a shift of paradigms.
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 900 tumor tissue samples as well as more than 400 normal tissue samples. This search resulted in more than 6 million peptide identifications, corresponding to more than 700.000 distinct peptides. Indeed, we could detect massively altered ligandome expression in every single tumor sample analyzed, including metabolomic changes. Regularly, every cancer expresses hundreds of HLA ligands that we could not find on any normal tissue, be it autologous or allogeneic. Such tumor specific ligands should be of tremendous use for the next generation of cancer immunotherapy. We already are involved in respective clinical trials.
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. These relations have now been carefully analyzed and interpreted in our recent publication in Genome Medicine (2019). Accordingly, far less than 1% of all somatic variants in a cancer will lead to HLA-presented neoantigens. These relevation is surprising for the majority in this field, and will lead to a shift of paradigms.
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 900 tumor tissue samples as well as more than 400 normal tissue samples. This search resulted in more than 6 million peptide identifications, corresponding to more than 700.000 distinct peptides. Indeed, we could detect massively altered ligandome expression in every single tumor sample analyzed, including metabolomic changes. Regularly, every cancer expresses hundreds of HLA ligands that we could not find on any normal tissue, be it autologous or allogeneic. Such tumor specific ligands should be of tremendous use for the next generation of cancer immunotherapy. We already are involved in respective clinical trials.