To model how immune-proficient and immune-deficient tumors evolved, Łuksza, Sethna, and Rojas et al. compared primary and recurrent tumors from long-term survivors (LTSs) and short-term survivors (STSs) of human pancreatic cancers and found that LTSs have fewer and more homogeneous recurrent tumors. LTS tumors contained both fewer new neoantigens and new clones, with markedly lower immune fitness cost compared with recurrent STS tumors. Mutations with a greater antigenic distance from self were more significantly depleted in LTS PDAC, suggesting that immune selection in LTS tumors edited clones with high-quality neoantigens.
Contributed by Shishir Pant
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.
Author Info: (1) Tisch Cancer Institute, Departments of Oncological Sciences and Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. marta.luksza@mssm.edu
Author Info: (1) Tisch Cancer Institute, Departments of Oncological Sciences and Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. marta.luksza@mssm.edu. (2) Computational Oncology Service, Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (3) Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (4) Computational Oncology Service, Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (5) Laboratoire de Physique de l'Ecole Normale Suprieure, ENS, Universit PSL, CNRS, Sorbonne Universit, Universit de Paris, Paris, France. Department of Mathematics, Imperial College London, London, UK. (6) Computational Oncology Service, Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (7) Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (8) Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (9) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (10) Computational Oncology Service, Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (11) Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (12) Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (13) Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (14) Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (15) Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (16) Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (17) Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (18) David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (19) David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (20) The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia. (21) The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia. University of Sydney, Sydney, New South Wales, Australia. (22) Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Swim Across America and Ludwig Collaborative Laboratory, Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (23) Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Swim Across America and Ludwig Collaborative Laboratory, Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (24) Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Swim Across America and Ludwig Collaborative Laboratory, Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (25) Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (26) Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (27) Laboratoire de Physique de l'Ecole Normale Suprieure, ENS, Universit PSL, CNRS, Sorbonne Universit, Universit de Paris, Paris, France. (28) Laboratoire de Physique de l'Ecole Normale Suprieure, ENS, Universit PSL, CNRS, Sorbonne Universit, Universit de Paris, Paris, France. (29) Laboratoire de Physique de l'Ecole Normale Suprieure, ENS, Universit PSL, CNRS, Sorbonne Universit, Universit de Paris, Paris, France. (30) Laboratoire de Physique de l'Ecole Normale Suprieure, ENS, Universit PSL, CNRS, Sorbonne Universit, Universit de Paris, Paris, France. (31) David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. (32) Computational Oncology Service, Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. greenbab@mskcc.org. Physiology, Biophysics & Systems Biology, Weill Cornell Medicine, Weill Cornell Medical College, New York, NY, USA. greenbab@mskcc.org. (33) Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. balachav@mskcc.org. Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. balachav@mskcc.org. David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA. balachav@mskcc.org. Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA. balachav@mskcc.org.
