The Predictive Value of Tumor Mutation Burden on Clinical Efficacy of Immune Checkpoint Inhibitors in Melanoma: A Systematic Review and Meta-Analysis

Ning, Biao; Liu, Yixin; Wang, Miao; Li, Yang; Xu, Tianzi; Wei, Yongchang

doi:10.3389/fphar.2022.748674

Cited by 41 publications

(35 citation statements)

References 65 publications

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“…Tumour mutational burden (TMB) refers to the total number of non-synonymous mutations observed per megabase ( 64 ), and it is a genomic biomarker with relatively low power to predict favourable responses to ICIs in melanoma ( 65 ). High TMB results in the expression of tumour related antigens, or neoantigens, that can trigger T cell activation.…”

Section: Discussionmentioning

confidence: 99%

Innate immune checkpoint inhibitor resistance is associated with melanoma sub-types exhibiting invasive and de-differentiated gene expression signatures

et al. 2022

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Melanoma is a highly aggressive skin cancer, which, although highly immunogenic, frequently escapes the body’s immune defences. Immune checkpoint inhibitors (ICI), such as anti-PD1, anti-PDL1, and anti-CTLA4 antibodies lead to reactivation of immune pathways, promoting rejection of melanoma. However, the benefits of ICI therapy remain limited to a relatively small proportion of patients who do not exhibit ICI resistance. Moreover, the precise mechanisms underlying innate and acquired ICI resistance remain unclear. Here, we have investigated differences in melanoma tissues in responder and non-responder patients to anti-PD1 therapy in terms of tumour and immune cell gene-associated signatures. We performed multi-omics investigations on melanoma tumour tissues, which were collected from patients before starting treatment with anti-PD1 immune checkpoint inhibitors. Patients were subsequently categorized into responders and non-responders to anti-PD1 therapy based on RECIST criteria. Multi-omics analyses included RNA-Seq and NanoString analysis. From RNA-Seq data we carried out HLA phenotyping as well as gene enrichment analysis, pathway enrichment analysis and immune cell deconvolution studies. Consistent with previous studies, our data showed that responders to anti-PD1 therapy had higher immune scores (median immune score for responders = 0.1335, median immune score for non-responders = 0.05426, p-value = 0.01, Mann-Whitney U two-tailed exact test) compared to the non-responders. Responder melanomas were more highly enriched with a combination of CD8+ T cells, dendritic cells (p-value = 0.03) and an M1 subtype of macrophages (p-value = 0.001). In addition, melanomas from responder patients exhibited a more differentiated gene expression pattern, with high proliferative- and low invasive-associated gene expression signatures, whereas tumours from non-responders exhibited high invasive- and frequently neural crest-like cell type gene expression signatures. Our findings suggest that non-responder melanomas to anti-PD1 therapy exhibit a de-differentiated gene expression signature, associated with poorer immune cell infiltration, which establishes a gene expression pattern characteristic of innate resistance to anti-PD1 therapy. Improved understanding of tumour-intrinsic gene expression patterns associated with response to anti-PD1 therapy will help to identify predictive biomarkers of ICI response and may help to identify new targets for anticancer treatment, especially with a capacity to function as adjuvants to improve ICI outcomes.

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Section: Discussionmentioning

confidence: 99%

Innate immune checkpoint inhibitor resistance is associated with melanoma sub-types exhibiting invasive and de-differentiated gene expression signatures

et al. 2022

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“…The results also provided a potential strategy of blocking other immune checkpoints for early-stage TNBC, including anti-CTLA-4 reagents, which are currently being used in mouse experiments and clinical trials for advanced BC (10,67,68). TMB and MSI predict a stronger response to ICI and prolonged survival in colorectal cancer, nonsmall cell lung cancer, and melanoma (69)(70)(71)(72). However, no differences in TMB or MSI were detected between two risk groups, possibly due to the rare incidence of non-synonymous mutations and mismatch repair in BC patients (11,12,27).…”

Section: Discussionmentioning

confidence: 99%

Immune landscape and risk prediction based on pyroptosis-related molecular subtypes in triple-negative breast cancer

Luo

Wang

et al. 2022

Front. Immunol.

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The survival outcome of triple-negative breast cancer (TNBC) remains poor, with difficulties still existing in prognosis assessment and patient stratification. Pyroptosis, a newly discovered form of programmed cell death, is involved in cancer pathogenesis and progression. The role of pyroptosis in the tumor microenvironment (TME) of TNBC has not been fully elucidated. In this study, we disclosed global alterations in 58 pyroptosis-related genes at somatic mutation and transcriptional levels in TNBC samples collected from The Cancer Genome Atlas and Gene Expression Omnibus databases. Based on the expression patterns of genes related to pyroptosis, we identified two molecular subtypes that harbored different TME characteristics and survival outcomes. Then, based on differentially expressed genes between two subtypes, we established a 12-gene score with robust efficacy in predicting short- and long-term overall survival of TNBC. Patients at low risk exhibited a significantly better prognosis, more antitumor immune cell infiltration, and higher expression of immune checkpoints including PD-1, PD-L1, CTLA-4, and LAG3. The comprehensive analysis of the immune landscape in TNBC indicated that alterations in pyroptosis-related genes were closely related to the formation of the immune microenvironment and the intensity of the anticancer response. The 12-gene score provided new information on the risk stratification and immunotherapy strategy for highly heterogeneous patients with TNBC.

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“…High TMB increases the chance that more T cells will recognize neoantigens, leading to clinically relevant better ICIs outcomes ( 17 ). MM patients with high TMB have more improvement in OS and progression-free survival (PFS) after receiving ICIs ( 18 , 19 ). UV exposure is thought to be the main cause of increased TMB in melanoma ( 20 , 21 ).…”

Section: Introductionmentioning

confidence: 99%

Gradient differences of immunotherapy efficacy in metastatic melanoma related to sunlight exposure pattern: A population-based study

Liu

et al. 2023

Front. Oncol.

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BackgroundImmune checkpoint inhibitors (ICIs) have revolutionized metastatic melanoma (MM) treatment in just a few years. Ultraviolet (UV) in sunlight is the most significant environmental cause of melanoma, which is considered to be the main reason for tumor mutation burden (TMB) increase in melanoma. High TMB usually predicts that PD-1 inhibitors are effective. The sunlight exposure pattern of MM might be a clinical feature that matches TMB. The relationship between sunlight exposure patterns and immunotherapy response in MM is unclear. This study aims to investigate the correlation between sunlight exposure patterns and immunotherapy response in MM and establish nomograms that predict 3- and 5-year overall survival (OS) rate.MethodsWe searched the Surveillance, Epidemiology, and End Results (SEER) database and enrolled MM cases from 2005-2016. According to the advent of ICIs in 2011, the era was divided into the non-ICIs era (2005-2010) and the ICIs era (2011-2016). Patients were divided into three cohorts according to the primary site sunlight exposure patterns: head and neck in the first cohort, trunk arms and legs in the second cohort, and acral sites in the third cohort. We compared survival differences for each cohort between the two eras, performed stratified analysis, established nomograms for predicting 3- and 5-year OS rate, and performed internal validation.ResultsComparing the survival difference between the ICIs and non-ICIs era, head and neck melanoma showed the greatest improvement in survival, with 3- and 5-year OS rate increasing by 10.2% and 9.1%, respectively (P=0.00011). In trunk arms and legs melanoma, the 3- and 5-year OS rate increased by 4.6% and 3.9%, respectively (P<0.0001). There is no improvement in survival in acral melanoma (AM) between the two eras (P=0.78). The receiver operating characteristic (ROC) curve, area under the ROC curve (AUC) and calibration graphs show good discrimination and accuracy of nomograms. Decision curve analysis (DCA) suggests good clinical utility of nomograms.ConclusionsBased on the classification of sunlight exposure patterns, there is a gradient difference in immunotherapy efficacy for MM. The degree of sunlight exposure is positively correlated with immunotherapy response. The nomograms are sufficiently accurate to predict 3- and 5-year OS rate for MM, allowing for individualized clinical decisions for future clinical work.

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The Predictive Value of Tumor Mutation Burden on Clinical Efficacy of Immune Checkpoint Inhibitors in Melanoma: A Systematic Review and Meta-Analysis

Cited by 41 publications

References 65 publications

Innate immune checkpoint inhibitor resistance is associated with melanoma sub-types exhibiting invasive and de-differentiated gene expression signatures

Innate immune checkpoint inhibitor resistance is associated with melanoma sub-types exhibiting invasive and de-differentiated gene expression signatures

Immune landscape and risk prediction based on pyroptosis-related molecular subtypes in triple-negative breast cancer

Gradient differences of immunotherapy efficacy in metastatic melanoma related to sunlight exposure pattern: A population-based study

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