Regulating the Immune Microenvironment in Breast Cancer

描述（由申请人提供）：尽管死亡率下降，但乳腺癌在与癌症有关的妇女死亡中排名第二。新辅助化疗越来越多地用于在手术前“缩小”肿瘤，并使乳房保守入路成为可能；然而，长期生存率仍然很低，部分原因是细胞毒性药物的疗效有限，不能完全消除转移细胞。因此，这些患者的医疗需求未得到满足，因为没有已知的有效治疗方法可以改善结果。虽然乳腺癌在历史上与潜在的炎症或感染没有联系，但它表现出肿瘤相关的炎症，其特征是白细胞浸润到发展中的肿瘤中，肿瘤基质中某些免疫细胞亚群的增加与疾病进展平行。然而，在大多数情况下，对癌症的天然免疫并不能起到保护作用，反而会促进疾病的发展。在乳腺癌发生的转基因小鼠模型中的研究表明，肿瘤相关巨噬细胞（tumor-associated macrophages, tam）通过在乳腺上皮细胞（MECs）中高水平表达表皮生长因子（epidermal growth factor， EGF）和激活EGF调控的信号传导来促进肿瘤生长和肺转移，而乳腺上皮细胞对肿瘤的侵袭性生长和转移传播至关重要。我们最近报道了表达白细胞介素(IL)-4的TH2 CD4+ T细胞通过直接调节TAM表型、生物效应功能和EGF表达来促进乳腺腺癌的侵袭和转移，进而调节肿瘤的侵袭性生长、循环肿瘤细胞（CTCs）的存在和转移。这些数据与临床研究结果相关联，揭示了乳腺癌通过炎症性TH2和调节性T （Treg）细胞反应逃避抗肿瘤免疫。基于这些数据，我们研究了阻断il - 4信号和中和TH2免疫是否会改变细胞毒治疗的疗效。我们发现，紫杉醇治疗的携带肿瘤的PyMT转基因小鼠缺乏IL4受体α (PyMT/IL4R1)，表现出延迟到终点（原发肿瘤大小）的增加，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，我们的研究目标是评估il4 /13调节轴在乳腺癌中功能调节促肿瘤免疫，从而促进癌细胞从保护性抗肿瘤免疫程序中逃逸的假设。为了验证这一假设，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轴的哪个组件代表抗癌治疗的最佳候选。阻断候选药物将通过评估抗肿瘤免疫应答来补充标准护理细胞毒疗法，单独或联合靶向阻断EGF受体（EGFR）或集落刺激因子(CSF)-1受体（CSF1R）激酶。这些研究将揭示在乳腺癌中中和促进肿瘤的th2型信号的治疗策略，当与细胞毒性或靶向治疗相结合时，产生多产的细胞毒性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.