The selective response of tumours to immune checkpoint blockade (ICB) therapy can be due to tumour-intrinsic features, such as mutational load in melanoma and lung cancer. Clear cell renal cell carcinoma (ccRCC) has a similar ICB response rate to these cancers despite having a much lower mutational load. Now, Miao et al. identify genomic alterations that influence the response of patients with metastatic ccRCC to ICB therapy with nivolumab (anti-PD1 antibody).
“We performed whole-exome and transcriptome profiling of paired tumour samples and normal tissues from 35 patients with ccRCC receiving ICB, followed by computational analysis to discern genomic features that were enriched in patients that responded to ICB therapy,” explains Eliezer Van Allen. The findings from the discovery cohort were confirmed by testing a validation cohort of 63 patients with metastatic ccRCC that were receiving ICB therapy.
Of seven genes that were recurrently mutated in ccRCC tumours, PBRM1, which encodes polybromo 1, was the only gene for which truncations or loss-of-function mutations were enriched in tumours of patients who showed clinical benefit from ICB therapy compared with patients who showed no clinical benefit. Notably, in patients who showed clinical benefit, truncating PBRM1 mutations always co-occurred with deletion of the non-mutated PBRM1 allele, consequently resulting in the loss of PBRM1 function. PBRM1 is a component of the PBAF subtype of the SWI/SNF chromatin remodelling complex. To determine how loss of PBRM1 enhances the response to ICB therapy, whole-transcriptome profiling data for a PBAF-deficient ccRCC cell line were analysed, revealingstrong enrichment of immunostimulatory genes (including genes involved in hypoxia response and JAK–STAT signalling) compared with PBAF-wild type ccRCC cell lines; these results were confirmed in PBRM1-loss-of-function tumours.
“chromatin dysregulation may be a new avenue towards understanding why patients with ccRCC ... respond to ICB”
“Taken together, these findings suggest that chromatin dysregulation may be a new avenue towards understanding why patients with ccRCC (and other types of cancer) respond to ICB,” says Van Allen. “This discovery warrants further experimental and clinical studies, including preclinical modelling in kidney cancer systems, as well as studies looking at ways to selectively inhibit PBRM1 or the PBAF complex, to improve our understanding of the molecular basis of responsiveness to immunotherapy.”
Miao, D. et al. Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science https://doi.org/10.1126/science.aan5951 (2018)
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Otto, G. PBRM1 loss promotes tumour response to immunotherapy. Nat Rev Nephrol 14, 142 (2018). https://doi.org/10.1038/nrneph.2018.7