Mutations in BRCA2 but not BRCA1 are associated with  tumours that respond well to immunotherapy, a US study has found.

In a surprising finding that has overturned assumptions about tumour responses to immunotherapy, researchers at Memorial Sloan Kettering Cancer Centre, New York, found divergent effects of BRCA1 and BRCA2 deficiency on the tumour microenvironment and immune responses in animal and human models.

In a paper in Nature Cancer, the researchers describe how they first investigated responses of BRCA2-deficient tumours cells from mice, which as expected showed significant growth delay in response to anti-PD-1 or combination anti-PD-1/anti-CTLA4 treatment. However, they saw a strikingly different effect in BRCA1 cell lines, with no such effect of immunotherapy.

Further experiments showed a distinct tumour immune microenvironment between BRCA1 and BRCA2 deficient human cells, with with gene expression programs related to both adaptive and innate immunity enriched in BRCA2-deficient tumours

“Single-cell RNA sequencing further revealed distinct T-cell, natural killer, macrophage and dendritic cell populations enriched in BRCA2-deficient tumours,” they noted.

They then examined responses to immunotherapy in a pan-cancer cohort of patients treated at the institution and confirmed differential responses with BRCA1 and BRCA2 mutations.

Following review of radiographic responses of identifiable patients, they noted a 44.4% rate of clinical benefit among patients receiving checkpoint inhibitor therapy with BRCA2 mutations across multiple cancer types (n=18). In other groups they noted that on univariable Cox regression analysis, BRCA2 mutations were associated with improved overall survical after immunotherapy (n=67; hazard ratio 0.48, 95% CI 0.29–0.80, P=0.004) relative to truncating mutations in BRCA1 (n=28; hazard ratio 0.76, 95% CI 0.48–1.54, P=0.45).

“To our knowledge, our study is the first to directly compare the effect of BRCA1 and BRCA2 loss on the microenvironment, and to provide evidence that they may have distinct consequences on tumour immunity and response to immune checkpoint blockade,” the authors said.

“Our results have important implications for the design of future clinical trials and highlight a possible fundamental difference in the mechanism by which these two canonical tumour suppressors mediate antitumour immunity,” they concluded.

The study authors said that when they started this work, they assumed that tumours with both types of homologous recombination deficiency would respond to immunotherapy based on having a high mutation burden, and the differential results for BRCA1 and BRCA2-mutated tumours were counterintuitive.

“Five years ago, people would’ve probably thought BRCA1 was going to be the more immunogenic tumour,” said study author Dr Nadeem Riaz.

“That’s because of the two types, BRCA1-mutant tumours tend to have higher number of immune cells inside them. You might expect that having more immune cells would mean a better response to immunotherapy. But in fact, it was the BRCA2-mutant tumours that showed the better response.”

With both BRCA1 and BRCA2  both involved in homologous recombination, and both leading to higher tumour mutation burden, the difference in response to immunotherapy may be due to BRCA1 creating different types of mutations that are not as readily detected by the immune system, the authors said.

The findings open up the possibility of using radiation targeted therapy in combination with other treatments such as immunotherapy, they added.

“While these new findings need to be confirmed by others and validated in clinical trials, they do suggest that people with BRCA2-mutant tumours may wish to consider enrolling in clinical trials of immunotherapy. Several trials are currently enrolling people with BRCA-mutant cancers,” they said.