相关阅读
乳腺癌易感基因（BRCA）是一种肿瘤抑制基因，发生突变后即失去肿瘤抑制作用，乳腺癌风险增加。其中，BRCA1突变患者多为难治型三阴性乳腺癌，对激素疗法、HER2靶向疗法无效。
2017年6月7日，美国科学促进会《科学》旗下《转化医学》封面及首篇发表澳大利亚沃尔特和伊丽莎·霍尔医学研究院、墨尔本大学、彼得麦卡伦癌症中心、皇家墨尔本医院、帕克维尔综合家族癌症中心、美国北卡罗来纳大学的研究报告，发现顺铂化疗＋双重免疫检查点抑制疗法对抑制小鼠乳腺癌生长，改善生存有显著作用，有望攻克BRCA1突变相关难治型三阴性乳腺癌。
沃尔特和伊丽莎·霍尔医学研究院：澳大利亚历史最悠久的医学研究机构，于1915年由澳大利亚慈善家沃尔特·罗素·霍尔之妻伊丽莎·霍尔在其丈夫去世后设立的基金捐建，与墨尔本大学、皇家墨尔本医院等合作密切。
免疫检查点：可对免疫系统进行自我检查、防止其过度激活的保护机制。正是由于这种保护机制存在，人体免疫系统才不会对自己的细胞、组织和器官进行攻击。然而，某些肿瘤细胞利用该机制逃避免疫系统监控与攻击，导致肿瘤在人体内疯狂生长。免疫检查点抑制疗法是利用患者自身免疫系统的新型癌症治疗方法，可擦亮免疫细胞的双眼，使其不被肿瘤麻痹，从而激活其对肿瘤的杀伤能力，对黑色素瘤、肺癌、膀胱癌等多种癌症有显著疗效，但是既往并未在乳腺癌领域取得显著成效。
该研究首先利用Brca1缺陷肿瘤模型分析了肿瘤的突变负荷、免疫谱、对免疫检查点抑制剂的反应。结果发现，与BRCA1野生型相比，BRCA1突变三阴性乳腺癌的突变负荷、肿瘤浸润性淋巴细胞数量、免疫调节相关基因（PDCD1/PD-1和CTLA4）表达均显著增加。随后，研究对Brca1缺陷小鼠使用顺铂化疗＋双重免疫检查点抑制疗法（抗PD-1和抗CTLA4），小鼠表现出强烈的全身和肿瘤局部免疫反应，并伴树突细胞激活、抑制性FOXP3+调节T细胞减少、肿瘤浸润细胞毒性CD8+和CD4+T细胞激活等。
不过，无论单纯使用双重免疫检查点抑制疗法，还是单纯使用顺铂化疗，并无上述显著疗效。这可能是由于化疗杀死的一些肿瘤细胞可将肿瘤抗原释放进入血液，方便免疫细胞进行识别，这反过来会增强免疫疗法的效果。
因此，顺铂＋双重免疫检查点抑制疗法可以显著抑制体内Brca1缺陷肿瘤生长并改善生存，该发现可为临床治疗BRCA1相关三阴性乳腺癌提供理论依据。
Sci Transl Med. 2017 Jun 7;9(393):eaal4922.
Combined immune checkpoint blockade as a therapeutic strategy for BRCA1-mutated breast cancer.
Nolan E, Savas P, Policheni AN, Darcy PK, Vaillant F, Mintoff CP, Dushyanthen S, Mansour M, Pang JB, Fox SB; Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab), Perou CM, Visvader JE, Gray DHD, Loi S, Lindeman GJ.
Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; University of Melbourne, Parkville, Victoria, Australia; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Parkville Integrated Familial Cancer Centre, Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Parkville, Victoria, Australia.
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.
PMID: 28592566
PII: eaal4922
DOI: 10.1126/scitranslmed.aal4922
联系客服
