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Article Dans Une Revue Nature Année : 2022

Neoantigen quality predicts immunoediting in survivors of pancreatic cancer

Marta Łuksza
  • Fonction : Auteur
Zachary Sethna
  • Fonction : Auteur
Luis Rojas
  • Fonction : Auteur
Jayon Lihm
Barbara Bravi
Yuval Elhanati
  • Fonction : Auteur
Kevin Soares
Masataka Amisaki
Anton Dobrin
  • Fonction : Auteur
David Hoyos
  • Fonction : Auteur
Pablo Guasp
Abderezak Zebboudj
Rebecca Yu
  • Fonction : Auteur
Adrienne Kaya Chandra
  • Fonction : Auteur
Theresa Waters
  • Fonction : Auteur
Zagaa Odgerel
  • Fonction : Auteur
Joanne Leung
  • Fonction : Auteur
Rajya Kappagantula
  • Fonction : Auteur
Alvin Makohon-Moore
Amber Johns
  • Fonction : Auteur
Anthony Gill
  • Fonction : Auteur
Mathieu Gigoux
Jedd Wolchok
Taha Merghoub
Michel Sadelain
Erin Patterson
  • Fonction : Auteur
Christine Iacobuzio-Donahue
Benjamin Greenbaum
Vinod Balachandran

Résumé

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.

Dates et versions

hal-04331950 , version 1 (08-12-2023)

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Marta Łuksza, Zachary Sethna, Luis Rojas, Jayon Lihm, Barbara Bravi, et al.. Neoantigen quality predicts immunoediting in survivors of pancreatic cancer. Nature, 2022, 606 (7913), pp.389-395. ⟨10.1038/s41586-022-04735-9⟩. ⟨hal-04331950⟩
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