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.

项目概要 尽管免疫检查点抑制剂（ICIs）前景广阔，但它对乳腺癌的影响有限 免疫系统与肿瘤细胞之间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 ICI 疗效的临床进展需要与能够诱导 微环境环境的广泛转变，这对于高度攻击性的人来说尤其重要 炎症性乳腺癌（IBC）是一种罕见且高度致命的乳腺癌，治疗选择很少。 在三阴性IBC患者的II期临床试验中，我们发现抗EGFR抗体帕尼单抗 （PmAb）与术前化疗相结合导致了较高的治疗反应。 IBC 模型中，PmAb 降低了免疫抑制趋化因子的表达并导致浸润增加 细胞毒性 T 细胞；表明从免疫抑制性 TME 到免疫反应性 TME 的广泛转变。 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，如果反过来，这种效应是观察到的现象的原因 IBC 中的免疫抑制 TME 已被检验为靶向肿瘤细胞的一种方法。 增殖和存活，据我们所知，没有其他小组研究过 EGFR 作为 TME 的调节剂 IBC。我们提出 3 个目标： 目标 1：确定 EGFR 通路调节的机制。 IBC 中的 TME 是通过 EGFR 途径诱导 IBC 中的免疫抑制性 TME。 EGR1 调节的免疫抑制趋化因子的表达我们将通过体外测定来检验这一假设。 以及我们的新型人源化 IBC 免疫活性小鼠模型 目标 2：评估组合。 我们勇敢地说，EGFR 靶向治疗将增强 IBC 的免疫治疗。 通过将 TME 从免疫抑制性转变为免疫反应性，免疫治疗在 IBC 中的疗效 我们将测试结合使用靶向 EGFR 和抑制免疫检查点的功效。 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 目标 3：确定 EGFR 调节的临床相关性。 我们捕获了 IBC 中 EGR1 表达的减少及其可能的转录靶点。 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。 将使用 IBC 基因组数据集和多重数据集评估我们途径的临床相关性 对 IBC 组织微阵列和正在进行的 PmAb 临床试验的 IBC 组织进行免疫染色。 完成后，我们期望确定 TME 变化，预测患者对 EGFR 靶向治疗的反应， 我们的研究为 IBC 患者建立了一种基于 EGFR 的新型联合疗法。 将拓宽我们对如何调节 TME 作为潜在治疗方法的理解。