Targeting the Progesterone Receptor as a Novel Means to Increase Efficacy of Immune Checkpoint Inhibitors in Hormone Receptor Positive Breast Cancer

靶向黄体酮受体作为提高激素受体阳性乳腺癌免疫检查点抑制剂疗效的新方法

• 批准号: 10512899
• 负责人: Christy Hagan
• 金额: $ 25.56万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-24 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10512899
• 关键词: Address; Anti-Progestin; Area; Binding; Cells; Cessation of life; Clinical; Data; Disease; Disease Resistance; Endocrine; Estrogen Antagonists; Estrogen Receptors; Estrogen receptor positive; Growth and Development function; Health; Human; Immune; Immune checkpoint inhibitor; Immunity; Immunologics; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Interferons; Intervention; Knowledge; Malignant Neoplasms; Mammary Neoplasms; Mediating; Mission; Modeling; Mus; Outcome; Pathway interactions; Precision therapeutics; Progesterone; Progesterone Receptors; Public Health; Refractory; Research; Resistance development; Role; STAT1 gene; Signal Pathway; Signal Transduction; T cell response; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Transgenic Organisms; Tumor Immunity; Tumor-Infiltrating Lymphocytes; Tumor-infiltrating immune cells; United States National Institutes of Health; Vaccines; Woman; anti-PD-1/PD-L1; anti-PD-L1; anti-PD-L1 antibodies; anti-PD-L1 therapy; base; breast cancer progression; efficacy testing; hormone receptor-positive; hormone therapy; immune checkpoint blockade; immune resistance; immunoregulation; improved; innovation; malignant breast neoplasm; mammary; neoplastic cell; new therapeutic target; novel; novel strategies; novel therapeutics; resistance mechanism; response; targeted treatment; therapeutic target; treatment response; tumor; tumor growth; tumor microenvironment; tumor-immune system interactions

ABSTRACT Approximately 75% of all breast cancers (BC) are classified as hormone receptor positive (HR+), the majority expressing both Estrogen and Progesterone Receptors (ER/PR). Although several classes of anti-estrogen endocrine therapies exist for these cancers, ~30% of women with ER+ breast cancer develop resistance and die from metastatic disease. Thus, new therapies are desperately needed for HR+ cancers, which constitute the majority of deaths from BC. While multiple therapies target ER and ER-signaling pathways, therapies targeting PR have not yet been employed, as its role in BC remains unclear. Our recent studies have revealed a significant immune modulatory role for PR in BC. Specifically, our early studies demonstrated a clear role for PR in suppressing cell intrinsic interferon responses through STAT1/2 inhibition. Recently, using transgenic PR models and orthotopic mouse PR+ BC lines, we demonstrated that PR expression results in enhanced tumor development and growth, which is dependent upon adaptive anti-tumor immunity, and altered immune infiltration into the mammary tumor microenvironment. These findings are congruent with clinical observations that HR+ BC have a striking reduction of tumor infiltrating lymphocytes in comparison to other BCs and are less responsive to immune checkpoint inhibitors (ICIs), such as anti-PD-L1 therapy. Thus, our past and current studies strongly suggest that HR+ BC immunosuppression is mediated by tumor cell PR expression and immunomodulation of the local tumor microenvironment (TME). We hypothesize that therapeutic targeting of PR will fundamentally alter the immunosuppressive mammary microenvironment and afford more robust responses of HR+ BC following treatment with ICIs. We will test this hypothesis in the following Aims: 1) Determine the anti-tumor utility of anti-progestins with anti-PD-L1 ICI as a means to elicit anti-tumor immunity against HR+ breast cancer. 2) Determine the anti-tumor utility of an optimal Ad-PR vaccine with anti-PD-L1 ICIs as a means to elicit anti-tumor immunity against HR+ breast cancer. These studies we will determine if blocking PR can activate localized anti-tumor immunity, thereby sensitizing HR+ breast cancers to treatment with ICIs. In our first aim, we will determine if anti-progestin blockade of PR signaling can reverse localized immunosuppression of PR+ mammary tumors and if this approach synergizes with ICI combinations. In our second aim, we will utilize a novel PR-targeting vaccine to stimulate T cell immunity against PR as a novel means to drive T cell infiltration into HR+ tumors and invigorate local anti-tumor immunity. The PR vaccine will be tested alone, and in combination with ICIs, as an additional approach to sensitive these tumors to treatment with ICIs. If successful, these studies could enable our understanding of PR immune modulation in BC and allow for new approaches to immunologically treat HR+ BC, which has been refractory to current immunotherapeutic interventions.

摘要 大约75%的乳腺癌(BC)被归类为激素受体阳性(HR+)，大多数 同时表达雌激素和孕激素受体(ER/PR)。虽然有几类抗雌激素药物 这些癌症有内分泌治疗方法，约30%的ER+乳腺癌妇女出现耐药和 死于转移性疾病。因此，迫切需要新的治疗方法来治疗HR+癌症，这构成了 大部分死于公元前。虽然多种疗法针对ER和ER-信号通路，但治疗 目标公关尚未被采用，因为它在不列颠哥伦比亚省的作用尚不清楚。我们最近的研究揭示了 PR在BC中具有重要的免疫调节作用。具体地说，我们早期的研究表明， PR通过抑制STAT1/2抑制细胞内源性干扰素反应。最近，使用转基因PR 模型和原位小鼠PR+BC系，我们证明PR的表达导致肿瘤增强 发育和生长依赖于适应性抗肿瘤免疫和改变的免疫 浸润性乳腺肿瘤微环境。这些发现与临床观察一致。 与其他BC相比，HR+BC的肿瘤浸润性淋巴细胞显著减少，并且 对免疫检查点抑制剂(ICIS)反应较差，如抗PD-L1治疗。因此，我们的过去和现在 研究表明，HR+BC免疫抑制是由肿瘤细胞PR表达和 局部肿瘤微环境的免疫调节(TME)。我们假设治疗靶点是 PR将从根本上改变免疫抑制的乳腺微环境，并提供更强大的 ICIS治疗后HR+BC的反应。我们将在以下目标中检验这一假设：1) 用抗PD-L1ICI作为诱导抗肿瘤免疫的手段确定抗孕激素的抗肿瘤效用 对抗HR+乳腺癌。2)确定抗PD-L1的最佳Ad-PR疫苗的抗肿瘤效果 ICIS作为一种诱导抗HR+乳腺癌抗肿瘤免疫的手段我们将确定这些研究是否 阻断PR可激活局部抗肿瘤免疫，从而使HR+乳腺癌对治疗敏感 和ICIS在一起。在我们的第一个目标中，我们将确定抗孕激素阻断PR信号是否可以逆转局部 PR+乳腺肿瘤的免疫抑制，以及这种方法是否与ICI联合应用协同作用。在我们的 第二个目的，我们将利用一种新型的PR靶向疫苗来刺激T细胞对PR的免疫作为一种新的 促进T细胞向HR+肿瘤的侵袭，增强局部抗肿瘤免疫。PR疫苗将会 单独测试，并与ICIS一起测试，作为对这些肿瘤的治疗敏感的另一种方法 和ICIS在一起。如果成功，这些研究可以使我们了解BC和BC的PR免疫调节 允许对HR+BC进行免疫治疗的新方法，这种方法对当前的 免疫治疗干预。