• 与BRCA1野生型三阴性乳腺癌(TNBCs)相比,BRCA1突变TNBCs 体细胞突变负荷增加,更多的肿瘤浸润淋巴细胞,免疫调控基因包括PDCD1 (PD-1) 和CTLA4表达增加;
  • 在Brca1缺陷小鼠中,顺铂联合双抗PD-1和抗CTLA4治疗有效地增强抗肿瘤免疫,导致明显的全身性和肿瘤内免疫应答;
  • 该应答包括树突状细胞活化增强,减少抑制性FOXP3(+) 调节T细胞,伴随肿瘤浸润细胞毒性CD8(+)和 CD4(+) T 细胞活性增强,特征为诱导多功能性产生细胞因子的T细胞。

Combined immune checkpoint blockade as a therapeutic strategy for BRCA1-mutated breast cancer



2017-06-07, Article

Abstract & Authors:展开

Immune checkpoint inhibitors have emerged as a potent new class of anticancer therapy. They have changed the treatment landscape for a range of tumors, particularly those with a high mutational load. To date, however, modest results have been observed in breast cancer, where tumors are rarely hypermutated. Because BRCA1-associated tumors frequently exhibit a triple-negative phenotype with extensive lymphocyte infiltration, we explored their mutational load, immune profile, and response to checkpoint inhibition in a Brca1-deficient tumor model. BRCA1-mutated triple-negative breast cancers (TNBCs) exhibited an increased somatic mutational load and greater numbers of tumor-infiltrating lymphocytes, with increased expression of immunomodulatory genes including PDCD1 (PD-1) and CTLA4, when compared to TNBCs from BRCA1-wild-type patients. Cisplatin treatment combined with dual anti-programmed death-1 and anti-cytotoxic T lymphocyte-associated antigen 4 therapy substantially augmented antitumor immunity in Brca1-deficient mice, resulting in an avid systemic and intratumoral immune response. This response involved enhanced dendritic cell activation, reduced suppressive FOXP3(+) regulatory T cells, and concomitant increase in the activation of tumor-infiltrating cytotoxic CD8(+) and CD4(+) T cells, characterized by the induction of polyfunctional cytokine-producing T cells. Dual (but not single) checkpoint blockade together with cisplatin profoundly attenuated the growth of Brca1-deficient tumors in vivo and improved survival. These findings provide a rationale for clinical studies of combined immune checkpoint blockade in BRCA1-associated TNBC.

First Authors:
,Peter Savas,Antonia N Policheni

Correspondence Authors:
Geoffrey J Lindeman

All Authors:
Emma Nolan,Peter Savas,Antonia N Policheni,Phillip K Darcy,François Vaillant,Christopher P Mintoff,Sathana Dushyanthen,Mariam Mansour,Jia-Min B Pang,Stephen B Fox, ,Charles M Perou,Jane E Visvader,Daniel H D Gray,Sherene Loi,Geoffrey J Lindeman