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 尽管有很大的前景，免疫粘液抑制剂（ICI）对乳腺癌的影响只有适中的影响 患者的生存。机械研究对免疫系统与肿瘤细胞之间的相互作用 确定肿瘤微环境（TME）是决定ICI对肿瘤的影响的关键因素 进展。 ICI效率的临床进步将需要与可以诱导A 微环境环境的广泛转变，这对于高度侵略性可能尤其重要 肿瘤。炎性乳腺癌（IBC）是一种罕见且高度致命的乳腺癌，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）结合术前化疗导致了很高的治疗反应。我们进一步发现 IBC模型，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；表明从免疫抑制转向免疫反应性TME。建立 这些初步发现，我们建议确定EGFR促进表达的机制 免疫抑制性趋化因子，如果此效果是造成观察到的 IBC中的免疫抑制TME。虽然已将EGFR抑制作用作为靶向肿瘤细胞的一种方式 据我们所知，扩散和生存，没有其他群体研究EGFR作为TME的调节器 IBC。我们提出3目标：目标1：确定EGFR途径调节的机制 IBC中的TME。我们假设EGFR途径通过IBC中的免疫抑制TME通过 免疫抑制趋化因子的EGR1调节表达。我们将通过体外测定法检验该假设 我们的新型人造IBC免疫能力小鼠模型。目标2：评估 IBC中EGFR抑制的免疫疗法。我们假设EGFR靶向疗法将增强 通过将TME从免疫抑制作用转移到免疫反应性，免疫疗法在IBC中的功效 表型。我们将测试靶向EGFR和抑制免疫检查点的效率 新型的IBC人源化小鼠模型和三阴性乳腺癌免疫能力小鼠模型 具有对ICIS的内在耐药性。 AIM 3：确定EGFR调制的临床相关性 TME在IBC中的变化。我们假设降低了EGR1的表达及其可能的转录靶标 与TME免疫反应状态相关，并预测IBC患者对基于PMAB的疗法的反应。我们 将使用IBC基因组数据集评估我们途径的临床相关性 在正在进行的PMAB临床试验中，在IBC组织微阵列和IBC组织上进行免疫染色。之上 完成，我们期望确定TME变化，以预测患者对EGFR靶向疗法的反应和 基于EGFR的IBC患者ICI的联合疗法。超越IBC，我们的研究 将扩大我们对如何将TME调节为潜在治疗方法的理解。