Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy Journal Article
| Authors: | Chowell, D.; Krishna, C.; Pierini, F.; Makarov, V.; Rizvi, N. A.; Kuo, F.; Morris, L. G. T.; Riaz, N.; Lenz, T. L.; Chan, T. A. |
| Article Title: | Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy |
| Abstract: | Functional diversity of the highly polymorphic human leukocyte antigen class I (HLA-I) genes underlies successful immunologic control of both infectious disease and cancer. The divergent allele advantage hypothesis dictates that an HLA-I genotype with two alleles with sequences that are more divergent enables presentation of more diverse immunopeptidomes1–3. However, the effect of sequence divergence between HLA-I alleles—a quantifiable measure of HLA-I evolution—on the efficacy of immune checkpoint inhibitor (ICI) treatment for cancer remains unknown. In the present study the germline HLA-I evolutionary divergence (HED) of patients with cancer treated with ICIs was determined by quantifying the physiochemical sequence divergence between HLA-I alleles of each patient’s genotype. HED was a strong determinant of survival after treatment with ICIs. Even among patients fully heterozygous at HLA-I, patients with an HED in the upper quartile respond better to ICIs than patients with a low HED. Furthermore, HED strongly impacts the diversity of tumor, viral and self-immunopeptidomes and intratumoral T cell receptor clonality. Similar to tumor mutation burden, HED is a fundamental metric of diversity at the major histocompatibility complex–peptide complex, which dictates ICI efficacy. The data link divergent HLA allele advantage to immunotherapy efficacy and unveil how ICI response relies on the evolved efficiency of HLA-mediated immunity. © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc. |
| Keywords: | cancer survival; controlled study; survival rate; gene mutation; major clinical study; overall survival; monotherapy; letter; tumor associated leukocyte; allele; cancer immunotherapy; cohort analysis; gene locus; genotype; t lymphocyte receptor; molecular evolution; clonal variation; hla a antigen; hla b antigen; hla c antigen; experimental design; non small cell lung cancer; metastatic melanoma; complementarity determining region; peptidomics; disease burden; human; priority journal; malignant neoplasm; immunological antineoplastic agent |
| Journal Title: | Nature Medicine |
| Volume: | 25 |
| Issue: | 11 |
| ISSN: | 1078-8956 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2019-11-01 |
| Start Page: | 1715 |
| End Page: | 1720 |
| Language: | English |
| DOI: | 10.1038/s41591-019-0639-4 |
| PUBMED: | 31700181 |
| PROVIDER: | scopus |
| PMCID: | PMC7938381 |
| DOI/URL: | |
| Notes: | Letter -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work