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

Su Yin Lim, Elena Shklovskaya, Jenny H. Lee, Bernadette Pedersen, Ashleigh Stewart, Zizhen Ming, Mal Irvine, Brindha Shivalingam, Robyn P. M. Saw, Alexander M. Menzies, Matteo S. Carlino, Richard A. Scolyer, Georgina V. Long, Helen Rizos*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)
82 Downloads (Pure)

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.

Original languageEnglish
Article number1516
Pages (from-to)1-18
Number of pages18
JournalNature Communications
Volume14
Issue number1
DOIs
Publication statusPublished - 18 Mar 2023

Bibliographical note

Copyright the Author(s) 2023. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Fingerprint

Dive into the research topics of 'The molecular and functional landscape of resistance to immune checkpoint blockade in melanoma'. Together they form a unique fingerprint.

Cite this