Lim and Shklovskaya et al. probed mechanisms of ICB resistance in paired tumor biopsies and cell lines from 18 patients with melanoma who were resistant to checkpoint therapy. The cell lines were highly heterogeneous: one was IFNγ unresponsive, while others had intrinsic IFNγ signaling, all with low immune infiltration. Half acquired a “de-differentiated” phenotype with loss of melanocyte antigens (e.g., Melan-A) and few activated and responsive T cells in biopsies and in vitro assays, respectively. Alterations in MHC-I/II (through CTIIA or B2M loss or epigenetic changes) were also common, and several lines, primarily from brain metastases, had PTEN deficiency.
Contributed by Alex Najibi
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 IFN_ 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.
Author Info: (1) Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia. Melanoma Institute Australia, The University of Sydney,
Author Info: (1) Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia. Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. (2) Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia. Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. (3) Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia. Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, NSW, Australia. (4) Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia. Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. (5) Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia. Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. (6) Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia. Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. (7) Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia. Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. (8) Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. Department of Neurosurgery, Chris O'Brien Lifehouse, Sydney, NSW, Australia. Department of Neurosurgery, Royal Prince Alfred Hospital, Sydney, NSW, Australia. (9) Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. Department of Melanoma and Surgical Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia. Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia. (10) Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia. Department of Medical Oncology, Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, NSW, Australia. Department of Medical Oncology, Mater Hospital, Sydney, NSW, Australia. (11) Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia. Department of Medical Oncology, Blacktown Cancer and Haematology Centre, Blacktown Hospital, Sydney, NSW, Australia. Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, NSW, Australia. (12) Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia. Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology, Sydney, NSW, Australia. Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia. (13) Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia. Department of Medical Oncology, Northern Sydney Cancer Centre, Royal North Shore Hospital, Sydney, NSW, Australia. Department of Medical Oncology, Mater Hospital, Sydney, NSW, Australia. Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia. (14) Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia. helen.rizos@mq.edu.au. Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. helen.rizos@mq.edu.au.
