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.

项目摘要 尽管前景广阔，但免疫检查点抑制剂（ICI）对乳腺癌的影响有限 患者的生存。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ICI对肿瘤影响的关键因素 进展ICI疗效的临床进展将需要与可以诱导免疫应答的药物组合。 微环境环境的广泛变化，这可能对高度侵略性的 肿瘤的炎症性乳腺癌（IBC）是一种罕见的高致死性乳腺癌，治疗选择很少。 在针对三阴性IBC患者的II期临床试验中，我们发现抗EGFR抗体帕尼单抗 （PmAb）联合术前化疗导致高治疗反应。我们进一步发现，在 在IBC模型中，PmAb降低免疫抑制趋化因子的表达，导致浸润增加 细胞毒性T细胞;提示从免疫抑制性TME到免疫反应性TME的广泛转变。基础上 这些初步的发现，我们建议确定EGFR促进表达的机制， 免疫抑制趋化因子，如果反过来，这种作用是负责观察到的 IBC中免疫抑制性TME。虽然EGFR抑制已被研究为靶向肿瘤细胞的一种方式， 增殖和生存，据我们所知，没有其他小组已经检查了EGFR作为TME的调节剂， IBC。我们提出了3个目标：目标1：确定EGFR通路调节细胞凋亡的机制。 IBC中的TME。我们假设EGFR途径通过以下途径诱导IBC中的免疫抑制性TME： EGR 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设 和我们的新型人源化IBC免疫活性小鼠模型。目标2：评估以下组合 在IBC中使用EGFR抑制的免疫疗法。我们假设EGFR靶向治疗将增强 通过将TME从免疫抑制性转变为免疫反应性， 表型我们将测试靶向EGFR和抑制免疫检查点的组合的功效， 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ICI有内在和后天的抵抗力。目的3：确定EGFR调节的肿瘤细胞的临床相关性。 IBC中的TME变化。我们假设EGR 1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PmAb治疗的反应。我们 将使用IBC基因组数据集和多路复用技术评估我们途径的临床相关性。 图10示出了来自正在进行的PmAb临床试验的IBC组织微阵列和IBC组织上的免疫染色。后 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的ICI联合治疗。除了IBC，我们的研究 将拓宽我们对如何调节TME作为潜在治疗方法的理解。