Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Department of Biomedical and Clinical Sciences "L. Sacco," Università degli Studi di Milano, Milan, Italy.
Cancer Res. 2021 Apr 15;81(8):2195-2206. doi: 10.1158/0008-5472.CAN-20-1659. Epub 2021 Jan 22.
Emerging evidence indicates that gut microbiota affect the response to anticancer therapies by modulating the host immune system. In this study, we investigated the impact of gut microbiota on immune-mediated trastuzumab antitumor efficacy in preclinical models of HER2-positive breast cancer and in 24 patients with primary HER2-positive breast cancer undergoing trastuzumab-containing neoadjuvant treatment. In mice, the antitumor activity of trastuzumab was impaired by antibiotic administration or fecal microbiota transplantation from antibiotic-treated donors. Modulation of the intestinal microbiota was reflected in tumors by impaired recruitment of CD4 T cells and granzyme B-positive cells after trastuzumab treatment. Antibiotics caused reductions in dendritic cell (DC) activation and the release of IL12p70 upon trastuzumab treatment, a mechanism that was necessary for trastuzumab effectiveness in our model. In patients, lower α-diversity and lower abundance of , and characterized nonresponsive patients (NR) compared with those who achieved pathologic complete response (R), similar to antibiotic-treated mice. The transfer of fecal microbiota from R and NR into mice bearing HER2-positive breast cancer recapitulated the response to trastuzumab observed in patients. Fecal microbiota β-diversity segregated patients according to response and positively correlated with immune signature related to interferon (IFN) and NO2-IL12 as well as activated CD4 T cells and activated DCs in tumors. Overall, our data reveal the direct involvement of the gut microbiota in trastuzumab efficacy, suggesting that manipulation of the gut microbiota is an optimal future strategy to achieve a therapeutic effect or to exploit its potential as a biomarker for treatment response. SIGNIFICANCE: Evidence of gut microbiota involvement in trastuzumab efficacy represents the foundation for new therapeutic strategies aimed at manipulating commensal bacteria to improve response in trastuzumab-resistant patients. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/8/2195/F1.large.jpg.
新兴证据表明，肠道微生物群通过调节宿主免疫系统来影响抗癌治疗的反应。在这项研究中，我们调查了肠道微生物群对曲妥珠单抗治疗 HER2 阳性乳腺癌的临床前模型和 24 例接受曲妥珠单抗联合新辅助治疗的原发性 HER2 阳性乳腺癌患者的免疫介导的抗肿瘤疗效的影响。在小鼠中，抗生素的给予或来自抗生素处理供体的粪便微生物群移植会损害曲妥珠单抗的抗肿瘤活性。曲妥珠单抗治疗后，肠道微生物群的调节反映在肿瘤中 CD4 T 细胞和颗粒酶 B 阳性细胞的募集受损。抗生素导致曲妥珠单抗治疗时树突状细胞 (DC) 的激活和 IL12p70 的释放减少，这是我们模型中曲妥珠单抗有效性所必需的机制。在患者中，与达到病理完全缓解 (R) 的患者相比，较低的 α-多样性和 、 和 的丰度较低，特征是无反应患者 (NR)，与接受抗生素治疗的小鼠相似。将 R 和 NR 患者的粪便微生物群转移到携带 HER2 阳性乳腺癌的小鼠中，可重现患者对曲妥珠单抗的反应。粪便微生物群的 β-多样性根据反应将患者分开，并与与干扰素 (IFN) 和 NO2-IL12 以及肿瘤中激活的 CD4 T 细胞和激活的 DC 相关的免疫特征呈正相关。总的来说，我们的数据揭示了肠道微生物群直接参与曲妥珠单抗疗效，表明操纵肠道微生物群是实现治疗效果或利用其作为治疗反应生物标志物的最佳未来策略。 意义：肠道微生物群参与曲妥珠单抗疗效的证据代表了旨在操纵共生细菌以提高曲妥珠单抗耐药患者反应的新治疗策略的基础。
