Development of a novel therapy targeting the tumor microenvironment in inflammatory breast cancer

开发针对炎性乳腺癌肿瘤微环境的新疗法

• 批准号: 10836263
• 负责人: Naoto T Ueno
• 金额: $ 58.15万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10836263
• 关键词: Adjuvant Chemotherapy; Animal Cancer Model; Antitumor Response; Breast Cancer Model; Breast Cancer Patient; CCL2 gene; CCL20 gene; CXCL5 gene; Cell Proliferation; Cell Survival; Clinical; Clinical Research; Clinical Trials; Color; Combination immunotherapy; Combined Modality Therapy; Cytotoxic T-Lymphocytes; Data; Development; Epidermal Growth Factor Receptor; Failure; Fc Receptor; Flow Cytometry; Genetic Transcription; Histologic; IL8 gene; Immune checkpoint inhibitor; Immune system; Immunocompetent; Immunotherapy; In complete remission; Infiltration; Inflammatory; Macrophage; Malignant Neoplasms; Neoadjuvant Therapy; Pathologic; Pathway interactions; Patients; Phase II Clinical Trials; Phenotype; Receptor Inhibition; Receptor Signaling; Regulation; Regulatory T-Lymphocyte; Research; Research Personnel; Resistance; Role; Testing; Therapeutic; Tissue Microarray; Tissues; anti-PD-L1 antibodies; anti-cancer; breast cancer genomics; checkpoint inhibition; chemokine; chemotherapy; clinically relevant; combinatorial; efficacy testing; genomic data; humanized mouse; immunoreactivity; in vitro Assay; in vivo; inflammatory breast cancer; malignant breast neoplasm; mouse model; neoplastic cell; new therapeutic target; novel; panitumumab; patient response; preclinical study; predicting response; prevent; single-cell RNA sequencing; targeted treatment; therapeutic target; transcription factor; treatment response; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumor progression; tumor-immune system interactions

PROJECT SUMMARY Despite great promise, immune checkpoint inhibitors (ICIs) have had only modest impact on breast cancer patients’ survival. Mechanistic studies into the interplay between the immune system and the tumor cells identified the tumor microenvironment (TME) as the critical factor in dictating the impact of ICIs on tumor progression. Clinical advancements in ICI efficacy will require combinations with agents that can induce a broad shift in the microenvironmental milieu, which may prove especially important for highly aggressive tumors. Inflammatory breast cancer (IBC) is a rare and highly lethal breast cancer with few therapeutic options. In phase II clinical trial for triple-negative IBC patients, we found that anti-EGFR antibody panitumumab (PmAb) combined with preoperative chemotherapy led to a high treatment response. We further found that in IBC models, PmAb reduced the expression of immunosuppressive chemokines and led to increased infiltration of cytotoxic T cells; suggesting a broad shift from an immunosuppressive to immunoreactive TME. Building on these preliminary findings, we propose to determine the mechanism by which EGFR promotes the expression of immunosuppressive chemokines and if, in turn, this effect is responsible for the observed immunosuppressive TME in IBC. While EGFR inhibition has been examined as a way to target tumor cell proliferation and survival, to our knowledge, no other group has examined EGFR as a modulator of the TME in IBC. We propose 3 aims: Aim 1: Determine the mechanism by which the EGFR pathway modulates the TME in IBC. We hypothesize that the EGFR pathway induces an immunosuppressive TME in IBC through EGR1-regulated expression of immunosuppressive chemokines. We will test this hypothesis via in vitro assays and our novel humanized IBC immunocompetent mouse model. Aim 2: Evaluate the combination of immunotherapy with EGFR inhibition in IBC. We hypothesize that EGFR-targeted therapy will enhance the efficacy of immunotherapy in IBC by shifting the TME from an immunosuppressive to an immunoreactive phenotype. We will test the efficacy of targeting EGFR and inhibiting immune checkpoints in combination using the novel IBC humanized mouse model and triple-negative breast cancer immunocompetent mouse models with intrinsic and acquired resistance to ICIs. Aim 3: Determine the clinical relevance of EGFR-modulated TME changes in IBC. We hypothesize that reduced expression of EGR1 and its likely transcriptional targets correlates with TME immunoreactive status and predicts IBC patient response to PmAb-based therapies. We will assess the clinical relevance of our pathway using an IBC genomic dataset and multiplexed immunostaining on an IBC tissue microarray and IBC tissues from an ongoing PmAb clinical trial. Upon completion, we expect to identify TME changes that predict patient response to EGFR-targeted therapy and establish a novel EGFR-based combination therapy with ICIs for patients with IBC. Beyond IBC, our research will broaden our understanding of how we can modulate the TME as a potential therapeutic approach.

项目总结 尽管前景看好，免疫检查点抑制剂(ICIS)对乳腺癌的影响并不大 病人的生存。免疫系统与肿瘤细胞相互作用的机制研究 确定肿瘤微环境(TME)是决定ICIS对肿瘤影响的关键因素 进步。ICI疗效的临床进步将需要与能够诱导 微环境环境的广泛变化，这可能被证明对高度攻击性特别重要 肿瘤。炎症性乳腺癌(IBC)是一种罕见的高度致命的乳腺癌，几乎没有治疗选择。 在三阴性IBC患者的II期临床试验中，我们发现抗EGFR抗体Panitumumab (PmAb)联合术前化疗有效率高。我们进一步发现，在 在IBC模型中，PmAb减少免疫抑制趋化因子的表达，并导致细胞浸润增加 指细胞毒性T细胞；暗示从免疫抑制到免疫反应的TME的广泛转变。在基础上建设 这些初步发现，我们建议确定EGFR促进表达的机制 免疫抑制趋化因子的作用，如果这一效应反过来导致观察到的 免疫抑制：IBC中的TME。虽然抑制EGFR已被检测为靶向肿瘤细胞的一种方式 增殖和存活，据我们所知，没有其他研究小组将EGFR作为TME的调节器 英国广播公司。我们提出了三个目标：目标1：确定EGFR途径调节细胞周期的机制。 在IBC的TME。我们假设EGFR途径通过以下途径在IBC中诱导免疫抑制的TME 表皮生长因子1调节免疫抑制趋化因子的表达。我们将通过体外试验来检验这一假说。 以及我们新的人源化IBC免疫活性小鼠模型。目标2：评估以下各项的组合 在IBC中应用EGFR抑制的免疫治疗。我们假设EGFR靶向治疗将增强 将TME从免疫抑制型转变为免疫反应型对IBC免疫治疗的疗效 表型。我们将测试靶向EGFR和抑制免疫检查点的效果，联合使用 新型IBC人源化小鼠模型和三阴性乳腺癌免疫活性小鼠模型 对ICIS具有内在和获得性耐药。目的3：确定EGFR调节的临床相关性 在IBC中发生变化。我们假设Egr1及其可能的转录靶点的表达减少 与TME免疫反应状态相关，并预测IBC患者对基于PmAb的治疗的反应。我们 将使用IBC基因组数据集和多路传输来评估我们的途径的临床相关性 正在进行的PmAb临床试验的IBC组织微阵列和IBC组织的免疫染色。vt.在.的基础上 完成后，我们希望确定TME的变化，预测患者对EGFR靶向治疗的反应 为IBC患者建立一种新的基于EGFR和ICIS的联合治疗。除了IBC，我们的研究 将拓宽我们对如何将TME作为一种潜在的治疗方法进行调节的理解。