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 and Helen Rizos ()
Additional contact information
Su Yin Lim: Macquarie University
Elena Shklovskaya: Macquarie University
Jenny H. Lee: Macquarie University
Bernadette Pedersen: Macquarie University
Ashleigh Stewart: Macquarie University
Zizhen Ming: Macquarie University
Mal Irvine: Macquarie University
Brindha Shivalingam: Melanoma Institute Australia, The University of Sydney
Robyn P. M. Saw: Melanoma Institute Australia, The University of Sydney
Alexander M. Menzies: Melanoma Institute Australia, The University of Sydney
Matteo S. Carlino: Melanoma Institute Australia, The University of Sydney
Richard A. Scolyer: Melanoma Institute Australia, The University of Sydney
Georgina V. Long: Melanoma Institute Australia, The University of Sydney
Helen Rizos: Macquarie University

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36979-y

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