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.

项目摘要 三阴性乳腺癌（TNBC）是乳腺癌最具侵略性的亚型，并且非常差 预后由于其转移和继电器的趋势。免疫检查点封锁（免疫疗法）加上 化学疗法是转移性TNBC的一线治疗方法，但肿瘤反应有限，而不是 耐用的。此外，缺乏强大的反应预测生物标志物仍然是一个限制因素 最大化免疫疗法的效率。因此，迫切需要开发更有效的 免疫疗法组合并建立新型的生物标志物，以识别将受益的TNBC患者 这种处理。因为肿瘤微环境（TME）严重影响TNBC对 免疫疗法，我们着手确定在TNBC中广泛介导的免疫激素的机制。我们的 初步研究表明，C-Jun N末端激酶（JNK）途径充当TME主开关 在TNBC中促进持续的免疫抑制TME。在这一证据的基础上，我们的中心假设是 JNK抑制剂（JNKI）通过从A的TNBC TME转换为免疫疗法 免疫抑制对免疫活性状态。我们的假设将通过3个特定目的进行检验：目标1） 确定JNK如何调节TNBC中的免疫抑制性TME和侵略性；目标2）建立 TNBC TME免疫抑制状态的JNK信号相关的生物标志物；目标3） TNBC的最佳JNKI免疫疗法组合。完成这些目标将提供强大的科学 为TNBC制定有效的治疗策略的框架。实验方法将是 以下内容：在AIM 1中，我们将研究JNK如何通过免疫学调节来促进TNBC侵略性 使用临床相关的免疫能力合成性TNBC小鼠模型具有明确定义的免疫 TMES。我们还将确定负责JNK对TME免疫学调节的分子。在AIM 2中， 我们将建立新型JNK信号相关的生物标志物，以反映TNBC的免疫抑制状态 TME使用患者样品。在AIM 3中，我们将测试JNKI是否通过TNBC中的免疫疗法协同作用 使用临床上相关的免疫能力TNBC小鼠模型促进免疫活性TME 以及我们已建立的TNBC分子亚型的患者衍生的Xenographographict（对敏感或抗性 免疫疗法）在人性化小鼠模型中。我们希望1）生成足够的临床前数据以支持 为TNBC患者和2）建立有效的JNKI免疫疗法组合的开发 TNBC TME的免疫抑制状态的生物标志物。拟议的研究很重要，因为 它从根本上将提高我们对癌症促进抑制的机制的理解 对免疫疗法的反应，并可能导致一种新型组合免疫疗法的发展 改善TNBC患者的存活率。