Regulating the Immune Microenvironment in Breast Cancer

描述(申请人提供)：尽管死亡率下降，但乳腺癌在女性癌症相关死亡中排名第二。新辅助化疗越来越多地用于在手术前缩小肿瘤，并使乳腺保守治疗成为可能；然而，长期存活率仍然很低，部分原因是细胞毒药物的疗效有限，无法完全消除转移细胞。因此，这些患者的医疗需求尚未得到满足，因为目前还没有已知的有效治疗方法来改善结果。虽然乳腺癌历史上并不与潜在的炎症或感染有关，但它表现出肿瘤相关性炎症，其特征是白细胞渗入正在发展的肿瘤，其中肿瘤间质中一些免疫细胞亚群的增加与疾病的进展平行。然而，在大多数情况下，对癌症的天然免疫力并不是保护性的，而是促进了疾病的发展。在转基因小鼠乳腺癌变模型中的研究表明，肿瘤相关巨噬细胞(TAMs)通过高水平表达表皮生长因子(EGF)并激活EGF调节的乳腺上皮细胞(MECs)信号通路，促进肿瘤生长和促进肺转移，MECs对肿瘤的侵袭和转移至关重要。我们最近报道，表达IL-4的TH2CD4T细胞通过直接调节的表型、生物效应功能和表皮生长因子的表达，促进乳腺癌的侵袭和转移，进而调节侵袭性肿瘤的生长、循环中肿瘤细胞的存在和转移。这些数据与揭示乳腺癌通过炎性TH2和调节性T(Treg)细胞反应逃避抗肿瘤免疫的临床研究结果相关联。基于这些数据，我们调查了阻断IL4信号和中和TH2免疫是否改变了细胞毒治疗的疗效。我们发现，经紫杉醇治疗的携带IL4受体α缺陷的PYMT转基因小鼠(PYMT/IL4R1)表现出到达终点(原发肿瘤大小)的潜伏期延长，同时肿瘤中CD8淋巴细胞的存在增加。基于这些令人兴奋的发现和令人信服的临床数据，我们研究的目标是评估这一假说，即IL4/13调节的轴在功能上调节乳腺癌的亲肿瘤免疫，从而促进癌细胞逃避保护性抗肿瘤免疫程序。为了评估这一假说，我们将阻断II型细胞因子IL4和IL13及其I型和II型受体的活性，并确定IL4/IL13轴的哪个成分代表抗癌治疗的最佳候选者。对候选药物的阻断将通过评估标准护理细胞毒疗法的抗肿瘤免疫反应来补充，这些疗法单独或与靶向阻断EGF受体(EGFR)或集落刺激因子-1受体(CSF1R)激酶结合使用。这些研究将揭示中和乳腺癌中促进肿瘤的TH2型信号的治疗策略，当与细胞毒或靶向治疗相结合时，产生有效的细胞毒反应和持久的肿瘤消退。

DESCRIPTION (provided by applicant): Despite declining mortality rates, breast cancer ranks second among cancer-related deaths of women. Neoadjuvant chemotherapy is increasingly used to "shrink" tumors prior to surgery and enable breast conservative approaches; however, long-term survival remains poor, in part due to limited efficacy of cytotoxic drugs that fail to completely eliminate metastatic cells. Thus, these patients have an unmet medical need since there is no known effective therapy that improves outcome. While breast cancer has not historically been linked to underlying inflammation or infection, it exhibits tumor-associated inflammation marked by infiltration of leukocytes into developing tumors where increases in some immune cell subsets in neoplastic stroma parallels disease progression. In the majority of cases however, the natural immunity to cancer that is present is not protective, but instead fosters disease progression. Studies in transgenic mouse models of mammary carcinogenesis have revealed that tumor-associated macrophages (TAMs) promote tumor growth and enhance pulmonary metastasis by high-level expression of epidermal growth factor (EGF) and activation of EGF-regulated signaling in mammary epithelial cells (MECs) critical for invasive tumor growth and metastatic dissemination. We recently reported that interleukin (IL)-4-expressing TH2 CD4+ T cells promote invasion and metastasis of mammary adenocarcinomas by directly regulating TAM phenotype, bioeffector function and EGF expression, that in turn regulate invasive tumor growth, presence of circulating tumor cells (CTCs) and metastasis. These data correlate with clinical findings revealing that breast cancers evade anti-tumor immunity by inflammatory TH2 and regulatory T (Treg) cell responses. Based on these data, we investigated whether blockade of IL4 signaling and neutralization of TH2 immunity altered efficacy of cytotoxic therapy. We found that Paclitaxel-treated tumor-bearing PyMT transgenic mice deficient for IL4 receptor alpha (PyMT/IL4R1) exhibited increased latency to endpoint (primary tumor size) accompanied by increased presence of CD8+ lymphocytes in tumors. Based on these exciting findings and compelling clinical data, the goal of our studies is to assess the hypothesis that an IL4/13-regulated axis functionally regulates pro-tumor immunity in breast cancers and thereby fosters cancer cell escape from protective anti-tumor immune programs. To evaluate this hypothesis, we will block the activities of the type II cytokines IL4 and IL13 and their type I and II receptors and determine which component of the IL4/IL13-axis represents the best candidate for anti-cancer therapy. Blockade of candidates will be complemented by evaluating anti-tumor immune responses to standard of care cytotoxic therapies, alone or in combination with targeted blockade of EGF receptor (EGFR) or colony stimulating factor (CSF)-1 receptor (CSF1R) kinases. These studies will reveal therapeutic strategies to neutralize tumor-promoting TH2-type signaling in breast cancers, that when combined with cytotoxic- or targeted therapy, engender productive cytotoxic responses and durable tumor regression.