Developing a novel combination immunotherapy for triple-negative breast cancer

开发针对三阴性乳腺癌的新型联合免疫疗法

• 批准号: 10734197
• 负责人: Naoto T Ueno
• 金额: $ 66.49万
• 依托单位: UNIVERSITY OF HAWAII AT MANOA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-18 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734197
• 关键词: Address; Biological Markers; Breast Cancer Patient; CCL2 gene; Cells; Clinical; Combination immunotherapy; Combined Modality Therapy; Data; Development; Goals; Immune; Immune response; Immuno-Chemotherapy; Immunocompetent; Immunohistochemistry; Immunologics; Immunotherapy; Knowledge; MAPK8 gene; MAPK9 gene; Macrophage; Malignant Neoplasms; Mediating; Mission; Myelogenous; N-terminal; Neoplasm Metastasis; Outcome; Paclitaxel; Pathway interactions; Patient-Focused Outcomes; Patients; Persons; Phosphotransferases; Prediction of Response to Therapy; Production; Prognosis; Protein Isoforms; Public Health; Relapse; Research; Resistance; Sampling; Scientific Advances and Accomplishments; Signal Transduction; Testing; Tissue Microarray; Tumor Tissue; Tumor-associated macrophages; Work; aggressive breast cancer; anti-PD1 antibodies; anticancer research; biomarker identification; chemotherapy; clinical translation; clinically relevant; cytokine; humanized mouse; immune checkpoint blockade; immunoregulation; improved; kinase inhibitor; malignant breast neoplasm; molecular subtypes; mouse model; neoplastic cell; neutrophil; novel; novel marker; patient derived xenograft model; potency testing; pre-clinical; predictive marker; recruit; response; response biomarker; single-cell RNA sequencing; standard of care; synergism; targeted agent; therapeutic biomarker; therapeutically effective; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions

PROJECT SUMMARY Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and has a very poor prognosis due to its tendency to metastasize and relapse. Immune checkpoint blockade (immunotherapy) plus chemotherapy is the first-line treatment for metastatic TNBC, but the tumor responses are limited and not durable. Additionally, the lack of robust predictive biomarkers of response remains a limiting factor in maximizing the efficacy of immunotherapy. Therefore, there is an urgent need to develop a more effective immunotherapy combination and establish novel biomarkers to identify TNBC patients who will benefit from this treatment. Because the tumor microenvironment (TME) critically influences TNBC response to immunotherapy, we set out to identify mechanisms that broadly mediate the immune response in TNBC. Our preliminary studies showed that the c-Jun N-terminal kinase (JNK) pathway acts as a TME master switch in promoting a persistent immunosuppressive TME in TNBC. Building on this evidence, our central hypothesis is that JNK inhibitors (JNKi) synergize with immunotherapy by converting the TNBC TME from an immunosuppressive to an immunoactive state. Our hypothesis will be tested through 3 specific aims: Aim 1) Determine how JNK regulates the immunosuppressive TME and aggressiveness in TNBC; Aim 2) Establish JNK signaling-related biomarkers of the immunosuppressive status of the TNBC TME; and Aim 3) Develop an optimal JNKi-immunotherapy combination for TNBC. Completing these aims will provide a robust scientific framework for developing effective therapeutic strategies for TNBC. The experimental approach will be as follows: In Aim 1, we will investigate how JNK promotes TNBC aggressiveness by immunologically modulating the TME using clinically relevant immunocompetent syngeneic TNBC mouse models with well-defined immune TMEs. We will also identify molecules responsible for JNK’s immunological modulation of the TME. In Aim 2, we will establish novel JNK signaling-related biomarkers reflecting the immunosuppressive status of the TNBC TME using patient samples. In Aim 3, we will test whether JNKi synergize with immunotherapy in TNBC by promoting an immunoactive TME, using clinically relevant immunocompetent syngeneic TNBC mouse models and our established patient-derived xenografts of TNBC molecular subtypes (sensitive or resistant to immunotherapy) in humanized mouse models. We expect to 1) generate sufficient preclinical data to support the development of an effective JNKi-immunotherapy combination for patients with TNBC and 2) establish biomarkers of the immunosuppressive status of the TNBC TME. The proposed research is significant because it will fundamentally advance our understanding of mechanisms by which cancers promote suppression of the response to immunotherapy and may lead to the development of a novel combination immunotherapy that improves the survival of TNBC patients.

项目概要 三阴性乳腺癌 (TNBC) 是乳腺癌中最具侵袭性的亚型，其复发率非常低 由于其转移和复发的倾向而导致的预后。免疫检查点阻断（免疫治疗）加上。 化疗是转移性TNBC的一线治疗方法，但肿瘤反应有限且不可行。 此外，缺乏可靠的反应预测生物标志物仍然是一个限制因素。 因此，迫切需要开发更有效的免疫疗法。 免疫治疗组合并建立新的生物标志物来识别将从中受益的 TNBC 患者 因为肿瘤微环境 (TME) 严重影响 TNBC 的反应。 免疫疗法，我们着手确定广泛介导 TNBC 免疫反应的机制。 初步研究表明，c-Jun N 末端激酶 (JNK) 通路充当 TME 主开关 基于这一证据，我们的中心假设是促进 TNBC 的持续免疫抑制 TME。 JNK 抑制剂 (JNKi) 通过将 TNBC TME 从 我们的假设将通过 3 个具体目标进行检验：目标 1) 确定 JNK 如何调节 TNBC 中的免疫抑制性 TME 和攻击性；目标 2) 建立； TNBC TME 免疫抑制状态的 JNK 信号相关生物标志物；目标 3) 开发一种 完成这些目标将为 TNBC 提供最佳的 JNKi 免疫治疗组合。 为 TNBC 的有效治疗策略制定框架。实验方法如下。 如下：在目标 1 中，我们将研究 JNK 如何通过免疫调节来促进 TNBC 的侵袭性 TME 使用具有明确免疫功能的临床相关免疫活性同基因 TNBC 小鼠模型 在目标 2 中，我们还将鉴定负责 JNK 免疫调节的分子。 我们将建立反映 TNBC 免疫抑制状态的新型 JNK 信号相关生物标志物 在目标 3 中，我们将使用患者样本来测试 JNKi 是否与 TNBC 中的免疫疗法具有协同作用。 使用临床相关的免疫活性同基因 TNBC 小鼠模型促进免疫活性 TME 以及我们建立的源自患者的 TNBC 分子亚型异种移植物（对 TNBC 分子亚型敏感或耐药） 免疫疗法）在人源化小鼠模型中，我们期望1）产生足够的临床前数据来支持。 为 TNBC 患者开发有效的 JNKi 免疫疗法组合，以及 2) 建立 TNBC TME 免疫抑制状态的生物标志物这项研究意义重大，因为。 它将从根本上增进我们对癌症促进抑制的机制的理解 对免疫疗法的反应，并可能导致新型联合免疫疗法的开发 提高 TNBC 患者的生存率。