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）是乳腺癌中最具侵袭性的亚型， 由于其转移和复发的倾向，预后不良。免疫检查点阻断（免疫疗法）加 化疗是转移性TNBC的一线治疗，但肿瘤反应有限， 耐用.此外，缺乏可靠的反应预测生物标志物仍然是治疗的限制因素。 最大限度地提高免疫治疗的功效。因此，迫切需要制定一个更有效的 免疫疗法组合和建立新的生物标志物以鉴定将受益于免疫疗法组合的TNBC患者。 这种待遇。由于肿瘤微环境（TME）严重影响TNBC对肿瘤的反应， 在免疫疗法中，我们着手鉴定广泛介导TNBC中的免疫应答的机制。我们 初步研究表明，c-Jun N-末端激酶（JNK）途径在TME中起着主开关的作用， 促进TNBC中持续的免疫抑制性TME。基于这些证据，我们的核心假设是 JNK抑制剂（JNKi）通过将TNBC TME从一种免疫抑制剂转化为另一种免疫抑制剂而与免疫疗法协同作用。 免疫抑制至免疫活性状态。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和侵袭性;目的2）建立 TNBC TME的免疫抑制状态的JNK信号传导相关的生物标志物;和目的3）开发一种用于TNBC TME的免疫抑制状态的JNK信号传导相关的生物标志物。 用于TNBC的最佳JNKi-免疫疗法组合。完成这些目标将提供一个强大的科学 为TNBC制定有效的治疗策略的框架。实验方法将作为 在目的1中，我们将研究JNK如何通过免疫调节来促进TNBC侵袭性， TME使用具有明确免疫功能的临床相关免疫活性同系TNBC小鼠模型， TME。我们还将鉴定负责JNK对TME的免疫调节的分子。在目标2中， 我们将建立新的JNK信号相关的生物标志物，反映TNBC的免疫抑制状态， 使用患者样本的TME。在目标3中，我们将通过以下方法测试JNKi是否与TNBC中的免疫疗法协同作用： 促进免疫活性TME，使用临床相关的免疫活性同基因TNBC小鼠模型 和我们建立的TNBC分子亚型的患者来源的异种移植物（对TNBC敏感或耐药）， 免疫疗法）。我们希望1）产生足够的临床前数据来支持 为TNBC患者开发有效的JNKi-免疫治疗组合，以及2）建立 TNBC TME的免疫抑制状态的生物标志物。这项研究意义重大，因为 它将从根本上推进我们对癌症促进抑制肿瘤细胞增殖的机制的理解。 对免疫疗法的反应，并可能导致开发一种新的联合免疫疗法， 提高TNBC患者的生存率。