Molecular determinants of resistance to immune checkpoint blockade in melanoma brain metastases

PD-1 and CTLA-4 are immune-inhibitory receptors (immune checkpoints) expressed mainly on T cells and NK cells. Their inhibition with function-blocking antibodies enhances anti-tumour responses, resulting in promising therapeutic efficacy in different cancers, including melanoma. ~60% of melanoma patients develop brain metastases (BrM), which are associated with poor prognosis. Recent clinical trials demonstrated a superior activity of combined PD-1/CTLA-4 (P/C) blockade in melanoma BrM as compared to the monotherapies. However, ~44% of patients fail to respond to P/C blockade, requiring further enhancement of the therapeutic efficacy. This requires a better understanding of the resistance mechanisms.
Using mouse melanoma BrM models, we have demonstrated a critical role of NK cells in the intracranial efficacy of P/C blockade (Taggart et al., 2018). We further identified differences in the transcriptional profiles (mRNAseq) of bulk tumours (BrM and skin tumours) and NK cells isolated from responders versus non-responders, as well as untreated control mice. We plan to perform an in-depth bioinformatics analysis of these preclinical data and publicly available patient data to shed light on the clinically relevant mechanisms of resistance to immune checkpoint blockade (ICB) in BrM and extracranial tumours, and to identify potential differences between the two sites.