Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy

Chowell, Diego; Krishna, Chirag; Pierini, Federica; Makarov, Vladimir; Rizvi, Naiyer A.; Kuo, Fengshen; Morris, Luc G.T.; Riaz, Nadeem; Lenz, Tobias; Chan, Timothy A.

doi:10.1038/s41591-019-0639-4

Cited by 239 publications

(263 citation statements)

References 56 publications

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“…Recently, sequence divergence of HLA was reported to be associated with anti-PD-1 efficacy 55 . In the present work, we demonstrated association between methylation of eDMRs targeting HLA and anti-PD-1 efficacy.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide identification of differentially methylated promoters and enhancers associated with response to anti-PD-1 therapy in non-small cell lung cancer

Cho¹,

Hong²,

Ha³

et al. 2020

Exp Mol Med

140

115

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Although approved programmed cell death protein (PD)-1 inhibitors show durable responses, clinical benefits to these agents are only seen in one-third of patients in most cancer types. Therefore, strategies for improving the response to PD-1 inhibitor for treating various cancers including non-small cell lung cancer (NSCLC) are urgently needed. Compared with genome and transcriptome, tumor DNA methylome in anti-PD-1 response was relatively unexplored. We compared the pre-treatment methylation status of cis-regulatory elements between responders and non-responders to treatment with nivolumab or pembrolizumab using the Infinium Methylation EPIC Array, which can profile ~850,000 CpG sites, including ~350,000 CpG sites located in enhancer regions. Then, we analyzed differentially methylated regions overlapping promoters (pDMRs) or enhancers (eDMRs) between responders and non-responders to PD-1 inhibitors. We identified 1007 pDMRs and 607 eDMRs associated with the anti-PD-1 response. We also identified 1109 and 1173 target genes putatively regulated by these pDMRs and eDMRs, respectively. We found that eDMRs contribute to the epigenetic regulation of the anti-PD-1 response more than pDMRs. Hypomethylated pDMRs of Cytohesin 1 Interacting Protein (CYTIP) and TNF superfamily member 8 (TNFSF8) were more predictive than programmed cell death protein ligand 1 (PD-L1) expression for anti-PD-1 response and progression-free survival (PFS) and overall survival (OS) in a validation cohort, suggesting their potential as predictive biomarkers for anti-PD-1 immunotherapy. The catalog of promoters and enhancers differentially methylated between responders and non-responders to PD-1 inhibitors presented herein will guide the development of biomarkers and therapeutic strategies for improving anti-PD-1 immunotherapy in NSCLC.

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Section: Discussionmentioning

confidence: 99%

Genome-wide identification of differentially methylated promoters and enhancers associated with response to anti-PD-1 therapy in non-small cell lung cancer

Cho¹,

Hong²,

Ha³

et al. 2020

Exp Mol Med

140

115

View full text Add to dashboard Cite

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“…The greater the number of neoantigens, the greater the extent of "non-Annals of Oncology EditorialUnderstanding other biological variables that affect immune activation, including host factors such as major histocompatibility presentation, will likely further strengthen the predictive value of TMB in the future[5]. Greater HLA diversity enables better control of both infectious disease and cancer following immune checkpoint therapy by expanding the size of the immunopeptidome[15]. Greater HLA diversity enables presentation of more neopeptides, and hence works in conjunction with TMB to enable immune checkpoint efficacy.…”

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confidence: 99%

The FDA approval of pembrolizumab for adult and pediatric patients with tumor mutational burden (TMB) ≥10: a decision centered on empowering patients and their physicians

et al. 2020

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“…The remarkable clinical response demonstrated by immune checkpoint inhibitors (ICIs) has led to a growing interest in understanding the interactions between cancer and immune cells 33,35,[55][56][57] . Although immunoediting is widely recognized as an evolutionary process that selects for clones with low immunogenicity or clones with an escape mechanism, its dynamics in the context of carcinogenesis and response to treatment are poorly understood.…”

Section: Discussionmentioning

confidence: 99%

“…These results engendered the concept of cancer immunoediting where tumor cells are subject to three phases: elimination, equilibrium, and escape 29 . Cancer immunoediting is an evolutionary process that shapes tumour immunogenicity by selecting for clones depleted of neoantigens (immune-adapted) or with an immune evasion phenotype (immune-escaped) [33][34][35] . Neoantigens are generated, among other mechanisms, by single nucleotide variants (SNVs) leading to aminoacidic changes in a peptide previously recognized as a self-antigen 36 .…”

Section: Introductionmentioning

confidence: 99%

dN/dSdynamics quantify tumour immunogenicity and predict response to immunotherapy

Zapata

Caravagna

Williams

et al. 2020

Preprint

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Immunoediting is a major force during cancer evolution that selects for clones with low immunogenicity (adaptation), or clones with mechanisms of immune evasion (escape). However, quantifying immunogenicity in the cancer genome and how the tumour-immune coevolutionary dynamics impact patient outcomes remain unexplored. Here we show that the ratio of nonsynonymous to synonymous mutations (dN/dS) in the immunopeptidome quantifies tumor immunogenicity and differentiates between adaptation and escape. We analysed 8,543 primary tumors from TCGA and validated immune dN/dS as a measure of selection associated with immune infiltration in immune-adapted tumours. In a cohort of 308 metastatic patients that received immunotherapy, pre-treatment lesions in non-responders showed increased immune selection (dN/dS<1), whereas responders did not and instead harboured a higher proportion of genetic escape mechanisms. Ultimately, these findings highlight the potential of evolutionary genomic measures to predict clinical response to immunotherapy.

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Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy

Cited by 239 publications

References 56 publications

Genome-wide identification of differentially methylated promoters and enhancers associated with response to anti-PD-1 therapy in non-small cell lung cancer

Genome-wide identification of differentially methylated promoters and enhancers associated with response to anti-PD-1 therapy in non-small cell lung cancer

The FDA approval of pembrolizumab for adult and pediatric patients with tumor mutational burden (TMB) ≥10: a decision centered on empowering patients and their physicians

dN/dSdynamics quantify tumour immunogenicity and predict response to immunotherapy

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