A neoantigen fitness model predicts tumour response to checkpoint blockade immunotherapy Journal Article
| Authors: | Luksza, M.; Riaz, N.; Makarov, V.; Balachandran, V. P.; Hellmann, M. D.; Solovyov, A.; Rizvi, N. A.; Merghoub, T.; Levine, A. J.; Chan, T. A.; Wolchok, J. D.; Greenbaum, B. D. |
| Article Title: | A neoantigen fitness model predicts tumour response to checkpoint blockade immunotherapy |
| Abstract: | Checkpoint blockade immunotherapies enable the host immune system to recognize and destroy tumour cells. Their clinical activity has been correlated with activated T-cell recognition of neoantigens, which are tumour-specific, mutated peptides presented on the surface of cancer cells. Here we present a fitness model for tumours based on immune interactions of neoantigens that predicts response to immunotherapy. Two main factors determine neoantigen fitness: The likelihood of neoantigen presentation by the major histocompatibility complex (MHC) and subsequent recognition by T cells. We estimate these components using the relative MHC binding affinity of each neoantigen to its wild type and a nonlinear dependence on sequence similarity of neoantigens to known antigens. To describe the evolution of a heterogeneous tumour, we evaluate its fitness as a weighted effect of dominant neoantigens in the subclones of the tumour. Our model predicts survival in anti-CTLA-4-treated patients with melanoma and anti-PD-1-treated patients with lung cancer. Importantly, low-fitness neoantigens identified by our method may be leveraged for developing novel immunotherapies. By using an immune fitness model to study immunotherapy, we reveal broad similarities between the evolution of tumours and rapidly evolving pathogens. © 2017 Author. |
| Keywords: | survival; controlled study; major clinical study; overall survival; somatic mutation; t lymphocyte; mass spectrometry; cytotoxic t lymphocyte antigen 4 antibody; cancer immunotherapy; immune system; cohort analysis; peptide; t lymphocyte receptor; amino acid sequence; sequence alignment; antigen recognition; disease duration; fitness; tumor; cross reaction; major histocompatibility complex; programmed death 1 receptor; non small cell lung cancer; tumor microenvironment; hydrophobicity; pathogen; cells and cell components; cancer; human; priority journal; article; gilvetmab |
| Journal Title: | Nature |
| Volume: | 551 |
| Issue: | 7681 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2017-11-23 |
| Start Page: | 517 |
| End Page: | 520 |
| Language: | English |
| DOI: | 10.1038/nature24473 |
| PROVIDER: | scopus |
| PUBMED: | 29132144 |
| PMCID: | PMC6137806 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 January 2018 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work