Epigenetic prediction of response to anti-PD-1 treatment in non-small-cell lung cancer: a multicentre, retrospective analysis

Duruisseaux, M.; Martínez-Cardús, Anna; Calleja-Cervantes, María Eréndira; Morán, Sebastian; Moura, Manuel Castro de; Dávalos, Verónica; Piñeyro, David; Sanchez-Cespedes, Montse; Girard, Nicolas; Brevet, Marie; Leprieur, Étienne Giroux; Duménil, Coraline; Pradotto, Monica; Bironzo, Paolo; Capelletto, Enrica; Novello, Silvia; Cortot, A.; Copin, Marie‐Christine; Karachaliou, Niki; González‐Cao, María; Peralta, Sergio; Montuenga, Luis M.; Gil-Bazo, Ignacio; Baraibar, Iosune; Lozano, Marı́a D.; Varela, Mar; Ruffinelli, J.C.; Palmero, Ramón; Nadal, Ernest; Morán, Teresa; Pérez, L.Mezquita; Ramos, Immaculada; Xiao, Qingyang; Fernández, Agustín F.; Fraga, Mario F.; Gut, Marta; Gut, Ivo; Teixidó, Cristina; Vilariño, Noelia; Prat, Aleix; Reguart, Noemı́; Benito, Amparo; Garrido, Pilar; Barragán, Isabel; Émile, Jean-François; Rosell, Rafael; Brambilla, Élisabeth; Esteller, Manel

doi:10.1016/s2213-2600(18)30284-4

Cited by 176 publications

(158 citation statements)

References 38 publications

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“…It has been pointed out recently that DNA hypomethylation promotes immune evasion in the corresponding tumors (Jung et al , 2019). Also, DNA methylation pattern predicting response to ICI treatment for non‐small‐cell lung cancer has been unveiled (Duruisseaux et al , 2018). Thus, further emphasis on DNA methylation for the distinction of different tumor microenvironments is warranted.…”

Section: Discussionmentioning

confidence: 99%

Analysis of DNA methylation patterns in the tumor immune microenvironment of metastatic melanoma

et al. 2020

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The presence of immune cells in the tumor microenvironment has been associated with response to immunotherapies across several cancer types, including melanoma. Despite its therapeutic relevance, characterization of the melanoma immune microenvironments remains insufficiently explored. To distinguish the immune microenvironment in a cohort of 180 metastatic melanoma clinical specimens, we developed a method using promoter CpG methylation of immune cell type-specific genes extracted from genome-wide methylation arrays. Unsupervised clustering identified three immune methylation clusters with varying levels of immune CpG methylation that are related to patient survival. Matching protein and gene expression data further corroborated the identified epigenetic characterization. Exploration of the possible immune exclusion mechanisms at play revealed likely dependency on MITF protein level and PTEN loss-of-function events for melanomas unresponsive to immunotherapies (immune-low). To understand whether melanoma tumors resemble other solid tumors in terms of immune methylation characteristics, we explored 15 different solid tumor cohorts from TCGA. Low-dimensional projection based on immune cell type-specific methylation revealed grouping of the solid tumors in line with melanoma immune methylation clusters rather than tumor types. Association of survival outcome with immune cell typespecific methylation differed across tumor and cell types. However, in melanomas immune cell type-specific methylation was associated with inferior patient survival. Exploration of the immune methylation patterns in a pan-cancer context suggested that specific immune microenvironments might occur across the cancer spectrum. Together, our findings underscore the existence of diverse immune microenvironments, which may be informative for future immunotherapeutic applications.

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Section: Discussionmentioning

confidence: 99%

Analysis of DNA methylation patterns in the tumor immune microenvironment of metastatic melanoma

et al. 2020

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“…Accumulating evidence indicates that innate immune cells play a role in the responsive TME and could be exploited therapeutically to improve outcomes. Relevant cells include macrophages (23)(24)(25), dendritic cells (DCs) (26) and natural killer (NK) cells (9,26). We will briefly discuss several cell types in the TME associated with response.…”

Section: Turning "Cold" Tumors "Hot"-cells In the Responsive Tmementioning

confidence: 99%

Sensitizing the Tumor Microenvironment to Immune Checkpoint Therapy

et al. 2020

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Immune checkpoint blockade (ICB) has revolutionized cancer treatment, providing remarkable clinical responses in some patients. However, the majority of patients do not respond. It is therefore crucial both to identify predictive biomarkers of response and to increase the response rates to immune checkpoint therapy. In this review we explore the current literature about the predictive characteristics of the tumor microenvironment and discuss therapeutic approaches that aim to change this toward a milieu that is conducive to response. We propose a personalized biomarker-based adaptive approach to immunotherapy, whereby a sensitizing therapy is tailored to the patient's specific tumor microenvironment, followed by on-treatment verification of a change in the targeted biomarker, followed by immune checkpoint therapy. By incorporating detailed knowledge of the immunological tumor microenvironment, we may be able to sensitize currently non-responsive tumors to respond to immune checkpoint therapy.

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“…Another recently reported microarray DNA methylation signature (EPIMMUNE) showed promising results in lung cancer, specifically for treatment with PD-1 blockade. This signature was also not associated with PD-L1 expression, the presence of CD8+ cells, or mutational load [71]. Innate resistance to anti-PD-1 treatment was found to be associated with a transcriptional signature referred to as IPRES, indicating concurrent upregulation of genes involved in mesenchymal transition, cell adhesion, extracellular matrix remodeling, angiogenesis, and wound healing [72].…”

Section: Discussionmentioning

confidence: 97%

Mass Spectrometry-Based Multivariate Proteomic Tests for Prediction of Outcomes on Immune Checkpoint Blockade Therapy: The Modern Analytical Approach

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et al. 2020

IJMS

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The remarkable success of immune checkpoint inhibitors (ICIs) has given hope of cure for some patients with advanced cancer; however, the fraction of responding patients is 15–35%, depending on tumor type, and the proportion of durable responses is even smaller. Identification of biomarkers with strong predictive potential remains a priority. Until now most of the efforts were focused on biomarkers associated with the assumed mechanism of action of ICIs, such as levels of expression of programmed death-ligand 1 (PD-L1) and mutation load in tumor tissue, as a proxy of immunogenicity; however, their performance is unsatisfactory. Several assays designed to capture the complexity of the disease by measuring the immune response in tumor microenvironment show promise but still need validation in independent studies. The circulating proteome contains an additional layer of information characterizing tumor–host interactions that can be integrated into multivariate tests using modern machine learning techniques. Here we describe several validated serum-based proteomic tests and their utility in the context of ICIs. We discuss test performances, demonstrate their independence from currently used biomarkers, and discuss various aspects of associated biological mechanisms. We propose that serum-based multivariate proteomic tests add a missing piece to the puzzle of predicting benefit from ICIs.

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Epigenetic prediction of response to anti-PD-1 treatment in non-small-cell lung cancer: a multicentre, retrospective analysis

Abstract: "Obra Social" La Caixa, Cellex Foundation, and the Health and Science Departments of the Generalitat de Catalunya.

Cited by 176 publications

References 38 publications

Analysis of DNA methylation patterns in the tumor immune microenvironment of metastatic melanoma

Analysis of DNA methylation patterns in the tumor immune microenvironment of metastatic melanoma

Sensitizing the Tumor Microenvironment to Immune Checkpoint Therapy

Mass Spectrometry-Based Multivariate Proteomic Tests for Prediction of Outcomes on Immune Checkpoint Blockade Therapy: The Modern Analytical Approach

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