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

• Published in: Nature communications 2023-03, Vol.14 (1), p.1516-1516, Article 1516
• Main Authors: Lim, Su Yin, Shklovskaya, Elena, Lee, Jenny H., Pedersen, Bernadette, Stewart, Ashleigh, Ming, Zizhen, Irvine, Mal, Shivalingam, Brindha, Saw, Robyn P. M., Menzies, Alexander M., Carlino, Matteo S., Scolyer, Richard A., Long, Georgina V., Rizos, Helen
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/109; 13/21; 13/31; 38/39; 631/67/1813/1634; 631/67/70; 82/1; 82/80; Antigen presentation; Antigens; Differentiation; Disruption; Flow cytometry; Functional analysis; Genomes; Humanities and Social Sciences; Humans; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immune system; Immunity, Innate; Immunotherapy; Immunotherapy - methods; Inhibitors; Innate immunity; Major histocompatibility complex; Melanoma; Melanoma - drug therapy; Melanoma - genetics; Melanoma - pathology; multidisciplinary; Patients; PTEN protein; Science; Science (multidisciplinary); Transcriptome; Transcriptomes; Tumor cell lines; Tumors; γ-Interferon
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-36979-y

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. Immunotherapy resistance is common among melanoma patients. Here, the authors identify three resistance mechanism subtypes across tumor-derived cell lines and matched samples and highlight antigen presentation disruption as a key mediator of resistance.