Targeting lymph node metastases to block cancer progression

利用淋巴结的力量产生持久的全身抗癌免疫反应， 从最近免疫疗法在一个癌症患者中的成功中可以看出， 患者的子集。然而，淋巴结转移的存在带来了更差的预后， 推荐用于大多数癌症患者的全身治疗。在过去的5年多里，我们的实验室已经证明， 除了作为癌症侵袭性的生物标志物之外，淋巴结转移以前 在癌症进展中未被认识到的作用，包括通过逃避淋巴结和远处种植 转移我们的初步数据还表明，转移性淋巴结是免疫抑制的，这导致 导致系统性抗癌免疫反应不良，并导致癌症进展。对于淋巴结患者 由于淋巴结转移，需要克服淋巴结的免疫抑制以获得成功的免疫治疗。为 建议的工作，我们已经产生了强有力的初步数据，两个互补的机制，我们 假设癌细胞在转移淋巴结中用于驱动免疫抑制。首先，我们的数据显示， 转移性淋巴结中的癌细胞亚群表达MHC II类分子，但不表达共刺激分子， 分子。我们假设MHCII阳性癌细胞与幼稚淋巴细胞的相互作用将导致 CD4 T细胞抑制和Treg形成，限制抗癌免疫应答（目的1）。我们将确定 转移性淋巴结中癌细胞上MHCII表达对抗癌免疫的影响 应答第二，我们的数据显示，由于淋巴结转移，淋巴细胞浸润有限。 高内皮微静脉的重塑。此外，我们发现氯沙坦治疗可以诱导淋巴细胞 浸润至淋巴结转移。在建议的工作中，我们将确定机制驱动 Losartan治疗后的淋巴细胞浸润，并测试这些浸润的淋巴细胞可以被 激活以促进抗癌免疫应答（Aim 2）。最后，为了产生抗癌免疫， 淋巴细胞活化（Aim 1）和浸润（Aim 2）均是针对转移性淋巴结病变的反应。 必需的.仅改善其中一种可能不足以驱动抗癌免疫反应。因此，我们将 测试抑制MHCII癌细胞表达以防止淋巴细胞抑制的翻译方法 联合氯沙坦诱导淋巴细胞浸润转移性淋巴结的免疫应答（目的 3）。我们的新研究计划将发现转移性淋巴瘤免疫抑制的关键机制， 节点以及开发治疗策略来克服这些机制。为了实现这些目标，我们 已经组建了一个世界级的淋巴结转移专家团队（T。Padera），免疫学（Mempel）， 癌症微环境（Jain）、系统生物学（Beyaz）、病理学（R. Padera），临床翻译（Taghian） 生物统计学（Lee）该小组的集体专长和资源将确保成功完成 提出的目标和探索新的治疗方法，转移性癌症患者。

Utilizing the power of lymph nodes to generate long-lasting, systemic anti-cancer immune responses has the potential to eradicate metastatic cancers from patients as seen with the recent success of immunotherapy in a subset of patients. The presence of lymph node metastases, however, brings with it a worse prognosis and the recommendation for systemic therapy for most cancer patients. Over the past 5+years our laboratory has shown that—beyond being a biomarker of the aggressiveness of the cancer—lymph node metastases play previously unrecognized roles in cancer progression, including by escaping the lymph node and seeding distant metastases. Our preliminary data also show that metastatic lymph nodes are immune suppressed, which leads to poor systemic anti-cancer immune responses and allows cancer progression. For patients with lymph node metastasis, immune suppression of lymph nodes needs to be overcome for successful immunotherapy. For the proposed work, we have generated strong preliminary data for two complementary mechanisms that we hypothesize cancer cells use in metastatic lymph nodes to drive immune suppression. First, our data show that a subset of cancer cells in metastatic lymph nodes express MHC class II molecules but not co-stimulatory molecules. We hypothesize that interactions of MHCII positive cancer cells with naïve lymphocytes will lead to CD4 T-cell suppression and Treg formation, limiting anti-cancer immune responses (Aim 1). We will determine the consequences of MHCII expression on cancer cells in metastatic lymph nodes for anti-cancer immune responses. Second, our data show limited lymphocyte infiltration into metastatic lesions in lymph nodes due to remodeling of high-endothelial venules. Further, we show that losartan treatment can induce lymphocyte infiltration into lymph node metastases. In the proposed work, we will determine the mechanism driving lymphocytic infiltration after losartan treatment and test the hypothesis that these infiltrated lymphocytes can be activated to promote anti-cancer immune responses (Aim 2). Finally, to generate an anti-cancer immune response against metastatic lymph node lesions, both lymphocytic activation (Aim 1) and infiltration (Aim 2) are required. Improving only one will likely not be sufficient to drive an anti-cancer immune response. Thus, we will test translational approaches to inhibit MHCII cancer cell expression to prevent suppression of lymphocytic immune response in combination with losartan to drive lymphocytic infiltration of metastatic lymph nodes (Aim 3). Our novel research program will discover critical mechanisms of immune suppression of metastatic lymph nodes as well as develop therapeutic strategies to overcome these mechanisms. To achieve these goals, we have assembled a world-class team of experts in lymph node metastasis (T. Padera), immunology (Mempel), cancer microenvironment (Jain), systems biology (Beyaz), pathology (R. Padera), clinical translation (Taghian) and biostatistics (Lee). The collective expertise and resources of the team will ensure successful completion of the proposed Aims and the exploration of novel treatment approaches for patients with metastatic cancer.