Neoantigen quality predicts immunoediting in survivors of pancreatic cancer

Cancer immunoediting 1 is a hallmark of cancer 2 that predicts that lymphocytes kill more immunogenic cancer cells to cause less immunogenic clones to dominate a population. Although proven in mice 1 , 3 , whether immunoediting occurs naturally in human cancers remains unclear. Here, to address this...

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Vydáno v:	Nature (London) Ročník 606; číslo 7913; s. 389 - 395
Hlavní autoři:	Łuksza, Marta, Sethna, Zachary M., Rojas, Luis A., Lihm, Jayon, Bravi, Barbara, Elhanati, Yuval, Soares, Kevin, Amisaki, Masataka, Dobrin, Anton, Hoyos, David, Guasp, Pablo, Zebboudj, Abderezak, Yu, Rebecca, Chandra, Adrienne Kaya, Waters, Theresa, Odgerel, Zagaa, Leung, Joanne, Kappagantula, Rajya, Makohon-Moore, Alvin, Johns, Amber, Gill, Anthony, Gigoux, Mathieu, Wolchok, Jedd, Merghoub, Taha, Sadelain, Michel, Patterson, Erin, Monasson, Remi, Mora, Thierry, Walczak, Aleksandra M., Cocco, Simona, Iacobuzio-Donahue, Christine, Greenbaum, Benjamin D., Balachandran, Vinod P.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 09.06.2022 Nature Publishing Group
Témata:	631/57/2266 631/67/580/1884 631/67/69 Antigens Cancer Cloning Discrimination Evolution Humanities and Social Sciences Hypotheses Immune system Immunogenicity Life Sciences Lymphocytes Lymphocytes T Major histocompatibility complex multidisciplinary Mutation Neoantigens Pancreatic cancer Peptides Physics Science Science (multidisciplinary) Survival T cell receptors Thymus gland Tumors
ISSN:	0028-0836, 1476-4687, 1476-4687
On-line přístup:	Získat plný text
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Popis
Shrnutí:	Cancer immunoediting 1 is a hallmark of cancer 2 that predicts that lymphocytes kill more immunogenic cancer cells to cause less immunogenic clones to dominate a population. Although proven in mice 1 , 3 , whether immunoediting occurs naturally in human cancers remains unclear. Here, to address this, we investigate how 70 human pancreatic cancers evolved over 10 years. We find that, despite having more time to accumulate mutations, rare long-term survivors of pancreatic cancer who have stronger T cell activity in primary tumours develop genetically less heterogeneous recurrent tumours with fewer immunogenic mutations (neoantigens). To quantify whether immunoediting underlies these observations, we infer that a neoantigen is immunogenic (high-quality) by two features—‘non-selfness’ based on neoantigen similarity to known antigens 4 , 5 , and ‘selfness’ based on the antigenic distance required for a neoantigen to differentially bind to the MHC or activate a T cell compared with its wild-type peptide. Using these features, we estimate cancer clone fitness as the aggregate cost of T cells recognizing high-quality neoantigens offset by gains from oncogenic mutations. With this model, we predict the clonal evolution of tumours to reveal that long-term survivors of pancreatic cancer develop recurrent tumours with fewer high-quality neoantigens. Thus, we submit evidence that that the human immune system naturally edits neoantigens. Furthermore, we present a model to predict how immune pressure induces cancer cell populations to evolve over time. More broadly, our results argue that the immune system fundamentally surveils host genetic changes to suppress cancer. The human immune system naturally edits cancers of high-quality neoantigens.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 PMCID: PMC9177421
ISSN:	0028-0836 1476-4687 1476-4687
DOI:	10.1038/s41586-022-04735-9