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The molecular and functional landscape of resistance to immune checkpoint blockade in melanoma.

ABSTRACT: Resistance to immune checkpoint inhibitor therapies in melanoma is common and remains an intractable clinical challenge. In this study, we comprehensively profile immune checkpoint inhibitor resistance mechanisms in short-term tumor cell lines and matched tumor samples from melanoma patients progressing on immune checkpoint inhibitors. Combining genome, transcriptome, and high dimensional flow cytometric profiling with functional analysis, we identify three distinct programs of immunotherapy resistance. Here we show that resistance programs include (1) the loss of wild-type antigen expression, resulting from tumor-intrinsic IFNγ signaling and melanoma de-differentiation, (2) the disruption of antigen presentation via multiple independent mechanisms affecting MHC expression, and (3) immune cell exclusion associated with PTEN loss. The dominant role of compromised antigen production and presentation in melanoma resistance to immune checkpoint inhibition highlights the importance of treatment salvage strategies aimed at the restoration of MHC expression, stimulation of innate immunity, and re-expression of wild-type differentiation antigens.

SUBMITTER: Lim SY

PROVIDER: S-EPMC10024679 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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The molecular and functional landscape of resistance to immune checkpoint blockade in melanoma.

Lim Su Yin SY Shklovskaya Elena E Lee Jenny H JH Pedersen Bernadette B Stewart Ashleigh A Ming Zizhen Z Irvine Mal M Shivalingam Brindha B Saw Robyn P M RPM Menzies Alexander M AM Carlino Matteo S MS Scolyer Richard A RA Long Georgina V GV Rizos Helen H

Nature communications 20230318 1

Resistance to immune checkpoint inhibitor therapies in melanoma is common and remains an intractable clinical challenge. In this study, we comprehensively profile immune checkpoint inhibitor resistance mechanisms in short-term tumor cell lines and matched tumor samples from melanoma patients progressing on immune checkpoint inhibitors. Combining genome, transcriptome, and high dimensional flow cytometric profiling with functional analysis, we identify three distinct programs of immunotherapy res ...[more]

PMID: 36934113

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Project description:BackgroundNumerous studies indicated that tumor-infiltrated immune cells (TIC) in the microenvironment are substantially linked to immunotherapy response and cancer prognosis. However, systematic studies of infiltrated immune cell characterization in uveal melanoma (UM) for prognosis and immune checkpoint blockade therapy are lacking.MethodsUM datasets were extracted from open access resources (TCGA and GEO databases). The tumor-infiltrated immune cells in the microenvironment were decoded by using the CIBERSORT algorithm, which was further applied to classify UM patients into subgroups using an unsupervised clustering method. The Boruta algorithm and principal component analysis were used to calculate the TIC scores for UM patients. Kaplan-Meier curves were plotted to prove the prognostic value of TIC scores. Besides, the correlations of the TIC score with clinical features, mutated characteristics, and the immune therapeutic response were subsequently investigated.ResultsAs a result, we defined three subtypes among 171 UM patients according to the TIC profiles and then calculated the TIC score to characterize the immune patterns for all patients. We discovered that high-TIC score patients with low BAP1 and high EIF1AX mutations have a better prognosis than low-TIC score patients. Activation of immune inflammatory response and increase in immune checkpoint-related genes in high-TIC score patients may account for good prognosis and immunotherapy response. Three melanoma cohorts received immunotherapy, proving that high-TIC score patients have substantial clinical and immune therapeutic improvements. Besides, several potential therapeutic agents were identified in the low-TIC score group.ConclusionOur study afforded a comprehensive view of infiltrated immune cell characterization to elucidate different immune patterns of UM. We also established a robust TIC-score signature, which may work as a prognostic biomarker and immune therapeutic predictor.

Dataset Information

The molecular and functional landscape of resistance to immune checkpoint blockade in melanoma.

Publications

The molecular and functional landscape of resistance to immune checkpoint blockade in melanoma.

Similar Datasets

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