Multiomic profiling of checkpoint inhibitor-treated melanoma: Identifying predictors of response and resistance, and markers of biological discordance

Newell, Felicity; Silva, Inês Pires da; Johansson, Peter; Menzies, Alexander M.; Wilmott, James S.; Addala, Venkateswar; Carlino, Matteo S.; Rizos, Helen; Nones, Kátia; Edwards, Jarem; Lakis, Vanessa; Kazakoff, Stephen H.; Mukhopadhyay, Pamela; Ferguson, Peter M.; Leonard, Conrad; Koufariotis, Lambros T.; Wood, Scott; Blank, Christian U.; Thompson, John F.; Spillane, Andrew J.; Saw, Robyn P.M.; Shannon, Kerwin F.; Pearson, John V.; Mann, Graham J.; Hayward, Nicholas K.; Scolyer, Richard A.; Waddell, Nicola; Long, Georgina V.

doi:10.1016/j.ccell.2021.11.012

Cited by 87 publications

(77 citation statements)

References 105 publications

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“…Transcriptomic analysis and immune profiling have revealed that the presence of EOMES + CD69 + CD45RO+ effector memory T cells and their gene expression profile was associated with response to ICI therapy [14]. In particular, high tumor mutation burden and interferon γ (IFNγ) signature are enriched in responders, while no prominent mechanisms of resistance were identified in a recent multiomics analysis of patient samples [15]. The efficacy of ICI seems to be affected not only by the number and type of effector T cells but also by their spatial distribution.…”

Section: Discussionmentioning

confidence: 99%

Prescription Patterns, Recurrence, and Toxicity Rates of Adjuvant Treatment for Stage III/IV Melanoma—A Real World Single-Center Analysis

Hoffmann

Hayoz

Özdemir

2022

Biology

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Approved adjuvant treatment options for stage III melanoma are the immune checkpoint inhibitors (ICI) pembrolizumab and nivolumab, and in presence of a BRAF V600E/K mutation additionally dabrafenib in combination with trametinib (BRAFi/MEKi). This study aims to describe prescription patterns and recurrence and toxicity rates of adjuvant-treated melanoma patients from the Cancer Center of the University Hospital Bern, Switzerland. One hundred and nine patients with an indication for adjuvant treatment were identified. Five (4.6%) had contraindications and, as such, were not proposed any adjuvant treatment, while 10 patients (9.2%) declined treatment. BRAF status was known for 91 (83.5%) patients. Of 40 (36.7%) patients with BRAF V600E/K melanoma, pembrolizumab was prescribed to 18 (45.0%), nivolumab to 16 (40.0%), and dabrafenib/trametinib to three (7.5%) patients. Grade 3–4 toxicity was reported in 18.9% and 16.7% of all the patients treated with pembrolizumab and nivolumab, respectively. No toxicities were observed for dabrafenib/trametinib. Thirty-eight percent of the patients treated with pembrolizumab and 40.0% of those treated with nivolumab relapsed. No relapses were reported for dabrafenib/trametinib. Prescription patterns indicate a clear preference for adjuvant ICI treatment.

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Section: Discussionmentioning

confidence: 99%

Prescription Patterns, Recurrence, and Toxicity Rates of Adjuvant Treatment for Stage III/IV Melanoma—A Real World Single-Center Analysis

Hoffmann

Hayoz

Özdemir

2022

Biology

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“…Efficacy of BRAF inhibitors depends on triggering a cancer cell death program associated with an impact on the tumor immune microenvironment 30 . Gene signatures related to interferon signaling, inflammation, and antigen presentation, which can enhance immune stimulation and response to checkpoint inhibitors 31 , were all induced by BRAFi treatment of control but not AR-overexpressing cells. A cross-connection has been established between BRAFi resistance and poor response to immune checkpoint control that does not depend on selection by the immune system and is a cancer cell-instructed 13 , in which increased AR expression may be involved.…”

Section: For a Comparison)mentioning

confidence: 99%

Androgen Receptor is a Determinant of Melanoma targeted drug resistance

Samarkina

Youssef

Ostano

et al. 2022

Preprint

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Melanoma provides a primary benchmark for targeted drug therapy. Most melanomas with BRAFV600 mutations regress in response to BRAF/MEK inhibitors (BRAFi/MEKi). However, nearly all relapse within the first two years, and there is a connection between pathways involved in BRAFi/MEKi-resistance and poor response to immune checkpoint therapy. We recently showed that androgen receptor (AR) activity is required for melanoma cell proliferation and tumorigenesis. Here we find that AR expression is markedly increased in BRAFi resistant melanoma cells as well as in sensitive cells soon after BRAFi exposure. Increased AR expression is by itself sufficient to render melanoma cells BRAFi-resistant, eliciting transcriptional changes of BRAFi resistant subpopulations and elevated EGFR and SERPINE1 expression of likely clinical significance. Inhibition of AR expression and activity blunts changes in gene expression and suppresses proliferation and tumorigenesis of BRAFi-resistant melanoma cells, enhances MHC I expression and CD8+ T cells infiltration. Our findings point to targeting AR as a possible co-adjuvant approach for the prevention and management of the disease.

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“…These results indicated that somatic mutations and relevant neoantigens showed no significant association with immunosuppressive TME. Recent studies on molecular characteristics of cancer patients treated with immune checkpoint inhibitors demonstrated that tumour mutational burden (TMB) and gene expression profile-based biomarkers, such as IFNγ-6-related and T cell-inflamed gene expression profiles, had a low correlation and thus were independently predictive of response [60][61][62][63]. These studies also indicated that these biomarkers combined with TMB could improve the prediction of response.…”

Section: Eic Shows No Difference In Tumour Mutational Burden or Numbe...mentioning

confidence: 99%

Identification of a cytokine-dominated immunosuppressive class in squamous cell lung carcinoma with implications for immunotherapy resistance

et al. 2022

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Background Immune checkpoint blockade (ICB) therapy has revolutionized the treatment of lung squamous cell carcinoma (LUSC). However, a significant proportion of patients with high tumour PD-L1 expression remain resistant to immune checkpoint inhibitors. To understand the underlying resistance mechanisms, characterization of the immunosuppressive tumour microenvironment and identification of biomarkers to predict resistance in patients are urgently needed. Methods Our study retrospectively analysed RNA sequencing data of 624 LUSC samples. We analysed gene expression patterns from tumour microenvironment by unsupervised clustering. We correlated the expression patterns with a set of T cell exhaustion signatures, immunosuppressive cells, clinical characteristics, and immunotherapeutic responses. Internal and external testing datasets were used to validate the presence of exhausted immune status. Results Approximately 28 to 36% of LUSC patients were found to exhibit significant enrichments of T cell exhaustion signatures, high fraction of immunosuppressive cells (M2 macrophage and CD4 Treg), co-upregulation of 9 inhibitory checkpoints (CTLA4, PDCD1, LAG3, BTLA, TIGIT, HAVCR2, IDO1, SIGLEC7, and VISTA), and enhanced expression of anti-inflammatory cytokines (e.g. TGFβ and CCL18). We defined this immunosuppressive group of patients as exhausted immune class (EIC). Although EIC showed a high density of tumour-infiltrating lymphocytes, these were associated with poor prognosis. EIC had relatively elevated PD-L1 expression, but showed potential resistance to ICB therapy. The signature of 167 genes for EIC prediction was significantly enriched in melanoma patients with ICB therapy resistance. EIC was characterized by a lower chromosomal alteration burden and a unique methylation pattern. We developed a web application (http://lilab2.sysu.edu.cn/tex & http://liwzlab.cn/tex) for researchers to further investigate potential association of ICB resistance based on our multi-omics analysis data. Conclusions We introduced a novel LUSC immunosuppressive class which expressed high PD-L1 but showed potential resistance to ICB therapy. This comprehensive characterization of immunosuppressive tumour microenvironment in LUSC provided new insights for further exploration of resistance mechanisms and optimization of immunotherapy strategies.

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Multiomic profiling of checkpoint inhibitor-treated melanoma: Identifying predictors of response and resistance, and markers of biological discordance

Cited by 87 publications

References 105 publications

Prescription Patterns, Recurrence, and Toxicity Rates of Adjuvant Treatment for Stage III/IV Melanoma—A Real World Single-Center Analysis

Prescription Patterns, Recurrence, and Toxicity Rates of Adjuvant Treatment for Stage III/IV Melanoma—A Real World Single-Center Analysis

Androgen Receptor is a Determinant of Melanoma targeted drug resistance

Identification of a cytokine-dominated immunosuppressive class in squamous cell lung carcinoma with implications for immunotherapy resistance

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