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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Veröffentlicht in:Nature (London) Jg. 606; H. 7913; S. 389 - 395
Hauptverfasser: 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.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 09.06.2022
Nature Publishing Group
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ISSN:0028-0836, 1476-4687, 1476-4687
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Abstract 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.
AbstractList 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.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.
Cancer immunoediting is a hallmark of cancer that predicts that lymphocytes kill more immunogenic cancer cells to cause less immunogenic clones to dominate a population. Although proven in mice , 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 , 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.
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.
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.
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.
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.
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. The human immune system naturally edits cancers of high-quality neoantigens.
Author Iacobuzio-Donahue, Christine
Hoyos, David
Balachandran, Vinod P.
Sethna, Zachary M.
Dobrin, Anton
Odgerel, Zagaa
Greenbaum, Benjamin D.
Wolchok, Jedd
Walczak, Aleksandra M.
Yu, Rebecca
Lihm, Jayon
Patterson, Erin
Gigoux, Mathieu
Leung, Joanne
Bravi, Barbara
Waters, Theresa
Zebboudj, Abderezak
Monasson, Remi
Kappagantula, Rajya
Chandra, Adrienne Kaya
Łuksza, Marta
Merghoub, Taha
Cocco, Simona
Soares, Kevin
Makohon-Moore, Alvin
Guasp, Pablo
Gill, Anthony
Rojas, Luis A.
Elhanati, Yuval
Mora, Thierry
Johns, Amber
Amisaki, Masataka
Sadelain, Michel
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  fullname: Łuksza, Marta
  email: marta.luksza@mssm.edu
  organization: Tisch Cancer Institute, Departments of Oncological Sciences and Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai
– sequence: 2
  givenname: Zachary M.
  surname: Sethna
  fullname: Sethna, Zachary M.
  organization: Computational Oncology Service, Department of Biostatistics, Memorial Sloan Kettering Cancer Center, Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center
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  givenname: Luis A.
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  organization: Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center
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  surname: Bravi
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  givenname: Yuval
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  organization: Computational Oncology Service, Department of Biostatistics, Memorial Sloan Kettering Cancer Center
– sequence: 7
  givenname: Kevin
  orcidid: 0000-0002-0406-017X
  surname: Soares
  fullname: Soares, Kevin
  organization: Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center
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  givenname: Masataka
  orcidid: 0000-0003-4153-4036
  surname: Amisaki
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  organization: Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center
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  givenname: Anton
  surname: Dobrin
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  organization: Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center
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  organization: Computational Oncology Service, Department of Biostatistics, Memorial Sloan Kettering Cancer Center
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  givenname: Pablo
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  surname: Guasp
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  givenname: Abderezak
  orcidid: 0000-0002-4708-5211
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  organization: Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center
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  givenname: Rebecca
  surname: Yu
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  organization: Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center
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  givenname: Adrienne Kaya
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  organization: Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center
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  givenname: Theresa
  surname: Waters
  fullname: Waters, Theresa
  organization: Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center
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  givenname: Zagaa
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  organization: Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center
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  surname: Kappagantula
  fullname: Kappagantula, Rajya
  organization: David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
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  orcidid: 0000-0002-4781-3565
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  organization: David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
– sequence: 20
  givenname: Amber
  surname: Johns
  fullname: Johns, Amber
  organization: The Kinghorn Cancer Centre, Garvan Institute of Medical Research
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  surname: Gill
  fullname: Gill, Anthony
  organization: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of Sydney
– sequence: 22
  givenname: Mathieu
  orcidid: 0000-0002-1831-7597
  surname: Gigoux
  fullname: Gigoux, Mathieu
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  surname: Patterson
  fullname: Patterson, Erin
  organization: Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center
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  surname: Monasson
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  organization: Laboratoire de Physique de l’Ecole Normale Supérieure, ENS, Université PSL, CNRS, Sorbonne Université, Université de Paris
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  givenname: Aleksandra M.
  surname: Walczak
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  organization: Laboratoire de Physique de l’Ecole Normale Supérieure, ENS, Université PSL, CNRS, Sorbonne Université, Université de Paris
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  orcidid: 0000-0002-4672-3023
  surname: Iacobuzio-Donahue
  fullname: Iacobuzio-Donahue, Christine
  organization: David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
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  email: greenbab@mskcc.org
  organization: Computational Oncology Service, Department of Biostatistics, Memorial Sloan Kettering Cancer Center, Physiology, Biophysics & Systems Biology, Weill Cornell Medicine, Weill Cornell Medical College
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  givenname: Vinod P.
  orcidid: 0000-0002-2956-223X
  surname: Balachandran
  fullname: Balachandran, Vinod P.
  email: balachav@mskcc.org
  organization: Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center
BackLink https://www.ncbi.nlm.nih.gov/pubmed/35589842$$D View this record in MEDLINE/PubMed
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Snippet 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...
Cancer immunoediting is a hallmark of cancer that predicts that lymphocytes kill more immunogenic cancer cells to cause less immunogenic clones to dominate a...
Cancer immunoediting1 is a hallmark of cancer2 that predicts that lymphocytes kill more immunogenic cancer cells to cause less immunogenic clones to dominate a...
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...
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StartPage 389
SubjectTerms 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
Title Neoantigen quality predicts immunoediting in survivors of pancreatic cancer
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