Neoantigen quality predicts immunoediting in survivors of pancreatic cancer

Marta Łuksza (), Zachary M. Sethna, Luis A. Rojas, Jayon Lihm, Barbara Bravi, Yuval Elhanati, Kevin Soares, Masataka Amisaki, Anton Dobrin, David Hoyos, Pablo Guasp, Abderezak Zebboudj, Rebecca Yu, Adrienne Kaya Chandra, Theresa Waters, Zagaa Odgerel, Joanne Leung, Rajya Kappagantula, Alvin Makohon-Moore, Amber Johns, Anthony Gill, Mathieu Gigoux, Jedd Wolchok, Taha Merghoub, Michel Sadelain, Erin Patterson, Remi Monasson, Thierry Mora, Aleksandra M. Walczak, Simona Cocco, Christine Iacobuzio-Donahue, Benjamin D. Greenbaum () and Vinod P. Balachandran ()
Additional contact information
Marta Łuksza: Icahn School of Medicine at Mount Sinai
Zachary M. Sethna: Memorial Sloan Kettering Cancer Center
Luis A. Rojas: Memorial Sloan Kettering Cancer Center
Jayon Lihm: Memorial Sloan Kettering Cancer Center
Barbara Bravi: Université PSL, CNRS, Sorbonne Université, Université de Paris
Yuval Elhanati: Memorial Sloan Kettering Cancer Center
Kevin Soares: Memorial Sloan Kettering Cancer Center
Masataka Amisaki: Memorial Sloan Kettering Cancer Center
Anton Dobrin: Memorial Sloan Kettering Cancer Center
David Hoyos: Memorial Sloan Kettering Cancer Center
Pablo Guasp: Memorial Sloan Kettering Cancer Center
Abderezak Zebboudj: Memorial Sloan Kettering Cancer Center
Rebecca Yu: Memorial Sloan Kettering Cancer Center
Adrienne Kaya Chandra: Memorial Sloan Kettering Cancer Center
Theresa Waters: Memorial Sloan Kettering Cancer Center
Zagaa Odgerel: Memorial Sloan Kettering Cancer Center
Joanne Leung: Memorial Sloan Kettering Cancer Center
Rajya Kappagantula: Memorial Sloan Kettering Cancer Center
Alvin Makohon-Moore: Memorial Sloan Kettering Cancer Center
Amber Johns: Garvan Institute of Medical Research
Anthony Gill: Garvan Institute of Medical Research
Mathieu Gigoux: Memorial Sloan Kettering Cancer Center
Jedd Wolchok: Memorial Sloan Kettering Cancer Center
Taha Merghoub: Memorial Sloan Kettering Cancer Center
Michel Sadelain: Memorial Sloan Kettering Cancer Center
Erin Patterson: Memorial Sloan Kettering Cancer Center
Remi Monasson: Université PSL, CNRS, Sorbonne Université, Université de Paris
Thierry Mora: Université PSL, CNRS, Sorbonne Université, Université de Paris
Aleksandra M. Walczak: Université PSL, CNRS, Sorbonne Université, Université de Paris
Simona Cocco: Université PSL, CNRS, Sorbonne Université, Université de Paris
Christine Iacobuzio-Donahue: Memorial Sloan Kettering Cancer Center
Benjamin D. Greenbaum: Memorial Sloan Kettering Cancer Center
Vinod P. Balachandran: Memorial Sloan Kettering Cancer Center

Nature, 2022, vol. 606, issue 7913, 389-395

Abstract: Abstract Cancer immunoediting1 is a hallmark of cancer2 that predicts that lymphocytes kill more immunogenic cancer cells to cause less immunogenic clones to dominate a population. Although proven in mice1,3, 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 antigens4,5, 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.

Date: 2022
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DOI: 10.1038/s41586-022-04735-9

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