Wound healing-like immune program facilitates postpartum mammary gland involution and tumor progression.
Wound healing-like immune program facilitates postpartum mammary gland involution and tumor progression.
复制标题
DOI：
10.1002/ijc.29181
复制
发表时间：
2015-04-15
影响因子：
6.4
通讯作者：
Schedin, Pepper
中科院分区：
文献类型：
--
作者：
Martinson, Holly A.;Jindal, Sonali;Durand-Rougely, Clarissa;Borges, Virginia F.;Schedin, Pepper
关键词：
产后5年内被诊断为乳腺癌的妇女存活率很低。在异种移植模型中，产后乳腺复旧的过程，即泌乳腺重塑到怀孕前的状态，促进了乳腺癌的进展。巨噬细胞内流发生在乳腺复旧期，暗示免疫调节促进了产后乳腺癌。在此，我们描述了产后小鼠乳腺的特征，并发现了与伤口愈合过程中发生的相似的免疫细胞的精心安排的流入。此外，正常的渐开线腺可能处于免疫抑制状态，这可以通过Foxp3+调节性T细胞和具有T细胞抑制功能的IL-10+巨噬细胞的短暂存在来识别。为了确定产后免疫微环境对乳腺肿瘤促进的影响，我们建立了一个免疫胜任模型。在该模型中，结痂组乳腺肿瘤比未结痂组肿瘤大6倍，CD4+和CD8+ T细胞浸润减少，含有更多巨噬细胞，具有抑制T细胞活化的能力。用一种针对免疫抑制细胞因子IL-10的中和抗体靶向衰老组小鼠的肿瘤生长，但在未生育小鼠中没有，这表明衰老微环境是αIL-10治疗的主要靶点。与女性相关，因为我们发现哺乳后的人类乳腺组织有短暂的高IL-10+和Foxp3+免疫细胞浸润。这些数据显示，正常内翻乳腺内存在免疫调节微环境，提示免疫抑制，当靶向时可减少肿瘤促进，揭示了产后乳腺癌可能的免疫基础策略。
Women diagnosed with breast cancer within 5 years postpartum have poor survival rates. The process of postpartum mammary gland involution, whereby the lactating gland remodels to its pre-pregnant state, promotes breast cancer progression in xenograft models. Macrophage influx occurs during mammary gland involution, implicating immune modulation in the promotion of postpartum breast cancer. Herein, we characterize the postpartum murine mammary gland and find an orchestrated influx of immune cells similar to that which occurs during wound healing. Further, the normal involuting gland may be in an immunosuppressed state as discerned by the transient presence of Foxp3+ regulatory T cells and IL-10+ macrophages with T cell suppressive function. To determine the influence of the postpartum immune microenvironment on mammary tumor promotion, we developed an immune-competent model. In this model, mammary tumors in the involution group are six-fold larger than nulliparous group tumors, have decreased CD4+ and CD8+ T cell infiltrates and contain a greater number of macrophages with the ability to inhibit T cell activation. Targeting involution with a neutralizing antibody against the immunosuppressive cytokine IL-10 reduces tumor growth in involution group mice but not in nulliparous mice, implicating the involution microenvironment as the primary target of αIL-10 treatment. Relevance to women is implicated, as we find post-lactational human breast tissue has transient high IL-10+ and Foxp3+ immune cell infiltrate. These data show an immune modulated microenvironment within the normal involuting mammary gland suggestive of immunosuppression, that when targeted reduces tumor promotion, revealing possible immune-based strategies for postpartum breast cancer.
登录
查看更多内容
影响因子：
15.9
作者：
Fadok, VA;Bratton, DL;Henson, PM
通讯作者：
Henson, PM
影响因子：
20.3
作者：
Movahedi, Kiavash;Guilliams, Martin;Van Ginderachter, Jo A.
通讯作者：
Van Ginderachter, Jo A.
影响因子：
11.2
作者：
Gupta, Piyush B.;Proia, David;Kuperwasser, Charlotte
通讯作者：
Kuperwasser, Charlotte
影响因子：
3.8
作者：
Callihan, Eryn B.;Gao, Dexiang;Jindal, Sonali;Lyons, Traci R.;Manthey, Elizabeth;Edgerton, Susan;Urquhart, Alexander;Schedin, Pepper;Borges, Virginia F.
通讯作者：
Borges, Virginia F.
影响因子：
82.9
作者：
通讯作者：
--