Breast Surgery, Hiroshima Mark Clinic, Hiroshima, Japan.
Breast Surgery, Hiroshima Mark Clinic, Hiroshima, Japan.
Eur J Surg Oncol. 2020 Jan;46(1):77-84. doi: 10.1016/j.ejso.2019.09.146. Epub 2019 Sep 18.
To evaluate immune responses paralleling the pathological and therapeutic effects of neoadjuvant chemotherapy (NAC) in the tumor microenvironment of breast cancer.
38 patients with stages II and III breast cancer received NAC followed by surgery in 2012-2018. Peripheral natural killer (pNK) cell activity, tumor-infiltrating lymphocytes (TILs), and levels of tumor microenvironmental factors were assessed before and after NAC.
In univariate analysis, grade 2 (G2) and better therapeutic effects were significantly associated with high post-NAC levels of NK cells and interleukin-6, and tended to be associated with higher CD4, CD8 and CTLA-4 transcripts. Disappearance of axillary lymph node metastasis (Ax+) was significantly associated with 1) increased NK and pNK levels, 2) decreased vascular endothelial growth factor (VEGF) transcripts after NAC, 3) the presence of ≥5% TILs, and tended to be associated with higher CTLA-4 levels before NAC. Multivariate analysis showed that G2 and better therapeutic effects were significantly associated with higher NK levels after NAC (OR = 1.07, 95% CI 1.00-1.14; p = 0.0255), and that disappearance of Ax+ was significantly associated with the presence of ≥5% pre-NAC TILs (OR = 19.87, 95% CI 2.24-175.80; p = 0.0072).
Increased NK cells after NAC, together with increased CD4 and CD8 T-cells, and decreased CTLA-4+ T cells and VEGF correlate with beneficial therapeutic effects. Systemic activation of pNK cell activity and the presence of pre-NAC TILs may improve the elimination of Ax + together with decreased immunosuppression by VEGF in tumors.
评估新辅助化疗（NAC）在乳腺癌肿瘤微环境中对病理和治疗效果的免疫反应。
2012 年至 2018 年期间，38 例 II 期和 III 期乳腺癌患者接受了 NAC 治疗，随后进行了手术。在 NAC 前后评估了外周自然杀伤（pNK）细胞活性、肿瘤浸润淋巴细胞（TILs）和肿瘤微环境因子水平。
在单因素分析中，G2 级及以上的治疗效果与 NAC 后 NK 细胞和白细胞介素-6 水平升高显著相关，且与 CD4、CD8 和 CTLA-4 转录物升高呈正相关。腋窝淋巴结转移（Ax+）消失与 1）NK 和 pNK 水平升高，2）NAC 后血管内皮生长因子（VEGF）转录物降低，3）存在≥5%的 TILs，且与 NAC 前 CTLA-4 水平升高相关。多因素分析显示，G2 级及以上的治疗效果与 NAC 后 NK 细胞水平升高显著相关（OR=1.07，95%CI 1.00-1.14；p=0.0255），Ax+消失与 NAC 前存在≥5%的 TILs 显著相关（OR=19.87，95%CI 2.24-175.80；p=0.0072）。
NAC 后 NK 细胞增加，同时 CD4 和 CD8 T 细胞增加，CTLA-4+T 细胞和 VEGF 减少与有益的治疗效果相关。pNK 细胞活性的全身性激活和 NAC 前 TILs 的存在可能会改善 Ax+的消除，并降低肿瘤中 VEGF 的免疫抑制作用。
