Brain microenvironment-driven resistance to immune and targeted therapies in acral melanoma

Rebecca J. Lee, Garima Khandelwal, Franziska Baenke, Alessio Caccistraci, Kenneth Macleod, Pivushkumar Mundra, Garry Ashton, Amit Mandal, Amaya Viros, Gabriela Gremel, Elena Galvani, Matthew Smith, Neil Carragher, Nathalie Dhomen, Crispin J. Miller, Paul Lorigan, Richard Marais

Research output: Contribution to journalArticlepeer-review


Combination treatments targeting the MEK-ERK pathway and checkpoint inhibitors have improved overall survival in melanoma. Resistance to treatment especially in the brain remains challenging, and rare disease subtypes such as acral melanoma are not typically included in trials. Here we present analyses from longitudinal sampling of a patient with metastatic acral melanoma that became resistant to successive immune and targeted therapy.

We performed whole-exome and RNA-sequencing on an acral melanoma that progressed on successive immune (nivolumab) and targeted (dabrafenib) therapy in the brain to identify resistance mechanisms. In addition, we performed growth inhibition assays, reverse phase protein arrays and immunoblotting on patient-derived cell lines using dabrafenib in the presence or absence of cerebrospinal fluid (CSF) in vitro. Patient derived xenografts were also developed to analyse response to dabrafenib.

Immune escape following checkpoint blockade was not due to loss of tumour cell recognition by the immune system or low neoantigen burden, but was associated with distinct changes in the microenvironment. Similarly, resistance to targeted therapy was not associated with acquired mutations but up-regulation of the AKT/PI3kinase pathway in the presence of cerebrospinal fluid.

Heterogeneous tumour interactions within the brain microenvironment enables progression on immune and targeted therapy and should be targeted in salvage treatments.

• What is already known about this subject?
Cutaneous melanoma brain metastases have been shown to respond to both immune and targeted therapies, however response and resistance in acral melanoma remains poorly characterised.
The PI3K pathway has been shown to be important in the brain, however its influence on response to treatment has not previously been tested using patient-derived models of melanoma and specifically acral melanoma brain metastases.
• What does this study add?
Despite low neoantigen burden, patients with acral melanoma can derive benefit from immune therapy. Immune therapy escape in the brain was not associated with mutational changes, however there was decreased infiltration of effector T cells, an increase in alternatively activated macrophages and distinct changes in gene expression, suggesting the brain microenvironment enabled immune escape. In addition, testing of patient derived xenografts and cell lines showed that resistance to targeted therapy in the brain was mediated by extrinsic factors resulting in activation of the PI3K/AKT pathway.

• How might this impact on clinical practice?
The PI3K/AKT pathway is an important target for melanoma brain metastases. Precision medicine must address the interactions of the tumour with the brain microenvironment and tailor therapies according to the site of progression in addition to its genomic features.
Original languageEnglish
JournalESMO Open
Early online date17 Aug 2020
Publication statusE-pub ahead of print - 17 Aug 2020


  • acral melanoma
  • immune therapy
  • targeted therapy
  • brain metastasis


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