改善三阴性乳腺癌免疫治疗疗效的组合疗法。
Combination therapies to improve the efficacy of immunotherapy in triple-negative breast cancer.
发表日期：2023 Sep 07
作者：
Maša Alečković, Zheqi Li, Ningxuan Zhou, Xintao Qiu, Bethlehem Lulseged, Pierre Foidart, Xiao-Yun Huang, Kodie Garza, Shaokun Shu, Nikolas Kesten, Rong Li, Klothilda Lim, Ana C Garrido-Castro, Jennifer L Guerriero, Jun Qi, Henry W Long, Kornelia Polyak
来源：
Epigenetics & Chromatin
摘要：
目前，联合化疗的免疫检查点抑制已经被批准作为一线治疗方案，用于晚期PD-L1阳性三阴性乳腺癌（TNBC）患者。然而，显著比例的转移性TNBC为PD-L1阴性，在这一人群中，仅使用化疗依然是标准的治疗方法，需要寻找新的治疗策略来改善临床效果。在这里，我们描述了一种三联治疗方法，包括抗PD-L1免疫检查点抑制、通过BET溴域抑制（BBDI）进行表观遗传改变，以及紫杉醇化疗，这种治疗方法有效抑制了两种不同的同种源小鼠TNBC模型中的原发性和转移性肿瘤生长。通过对单独和联合治疗组的肿瘤进行详细的细胞和分子分析，发现在接受三联治疗的小鼠中，增加了T细胞和B细胞浸润，并且使巨噬细胞从M1型转变为M2型。三联治疗还对基因表达和染色质进行了重要的影响，使细胞转变为更具免疫原性和衰老状态。我们的研究结果提供了强有力的临床前证据，支持对BBDI、紫杉醇和免疫检查点抑制联合治疗进行临床试验。
Immune checkpoint inhibition combined with chemotherapy is currently approved as first-line treatment for patients with advanced PD-L1-positive triple-negative breast cancer (TNBC). However, a significant proportion of metastatic TNBC is PD-L1-negative and, in this population, chemotherapy alone largely remains the standard-of-care and novel therapeutic strategies are needed to improve clinical outcomes. Here, we describe a triple combination of anti-PDL-1 immune checkpoint blockade, epigenetic modulation thorough BET bromodomain inhibition (BBDI), and chemotherapy with paclitaxel that effectively inhibits both primary and metastatic tumor growth in two different syngeneic murine models of TNBC. Detailed cellular and molecular profiling of tumors from single and combination treatment arms revealed increased T and B cell infiltration and macrophage reprogramming from M1 to a M2 phenotype in mice treated with triple combination. Triple combination also had a major impact on gene expression and chromatin profiles shifting cells to a more immunogenic and senescent state. Our results provide strong preclinical evidence to justify clinical testing of BBDI, paclitaxel, and immune checkpoint blockade combination.