Research Article: Association of BRCA1- and BRCA2-deficiency with mutation burden, expression of PD-L1/PD-1, immune infiltrates, and T cell-inflamed signature in breast cancer

Date Published: April 25, 2019

Publisher: Public Library of Science

Author(s): Wei Xiong Wen, Chee-Onn Leong, Peiwen Fei.


Immune checkpoint inhibitors have demonstrated effective anti-tumour response in cancer types with high mutation burden (e.g. melanoma) and in subset of cancers with features of genomic instability (e.g. mismatch-repair deficiency). One possible explanation for this effect is the increased expression of immune checkpoint molecules and pre-existing adaptive immune response in these cancers. Given that BRCA1 and BRCA2 are integral in maintaining genomic integrity, we hypothesise that the inactivation of these genes may give rise to breast cancers with such immunogenic phenotype. Therefore, using two large series of publicly available breast cancer datasets, namely that from The Cancer Genome Atlas and Wellcome Trust Institute, we sought to investigate the association between BRCA1- and BRCA2-deficiency with features of genomic instability, expression of PD-L1 and PD-1, landscape of inferred tumour-infiltrating immune cells, and T-cell inflamed signature in breast cancers. Here, we report that BRCA1 and BRCA2-deficient breast cancers were associated with features of genomic instability including increased mutation burden. Interestingly, BRCA1-, but not BRCA2-, deficient breast cancers were associated with increased expression of PD-L1 and PD-1, higher abundance of tumour-infiltrating immune cells, and enrichment of T cell-inflamed signature. The differences in immunophenotype between BRCA1- and BRCA2-deficient breast cancers can be attributed, in part, to PTEN gene mutation. Therefore, features of genomic instability such as that mediated by BRCA1- and BRCA2- deficiency in breast cancer were necessary, but not always sufficient, for yielding T cell-inflamed tumour microenvironment, and by extension, predicting clinical benefit from immunotherapy.

Partial Text

Immunotherapy using immune checkpoint blockade such as that of PD-1, PD-L1, and CTLA-4 inhibitors have demonstrated durable anti-tumour response in several cancer types including melanoma [1, 2], non-small cell lung carcinoma [3–5], head and neck squamous cell carcinoma [6], urothelial carcinoma [7], renal-cell carcinoma [8], and Hodgkin lymphoma [9]. Accordingly, selected immune checkpoint inhibitors have been approved by the US Food and Drug Administration (FDA) and European Medicine Agency (EMA) for the treatment of these cancers. Various predictors were found to be positively correlated with response to immune checkpoint inhibitors, in particular anti-PD-1 antibody, including high mutation burden and neoantigen load, increased expression of PD-L1, and increased expression of IFN-γ-responsive genes [7, 10–14]. Furthermore, biomarkers of genomic instability such as mismatch-repair deficiency and DNA repair pathway mutations including POLE, POLD1, and MSH2 gave rise to similar genomic features and immunophenotype predictive of response to immunotherapy in several cancer types [12, 15, 16]. Collectively, these studies suggest that high mutation burden as a result of genomic instability and the consequent increased in tumour surface neoantigens leads to an increased in tumour-infiltrating immune cells and ultimately the compensatory up-regulation of the PD-1/PD-L1 pathway as a mechanism of inhibiting T-cell activation at tumour sites [17, 18].

In this study, we investigated the features of genomic instability, expression of checkpoint molecules, and T cell-inflamed signature stratified by BRCA1- and BRCA2-deficiency status in two large series of breast cancer patients.




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