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.

抽象的 大约 75% 的乳腺癌 (BC) 被归类为激素受体阳性 (HR+)，其中大多数 表达雌激素和孕激素受体 (ER/PR)。尽管有几类抗雌激素药物 这些癌症存在内分泌疗法，约 30% 的 ER+ 乳腺癌女性会产生耐药性，并且 死于转移性疾病。因此，HR+癌症迫切需要新的疗法，这些癌症构成了 BC 省的大部分死亡病例。虽然多种疗法针对 ER 和 ER 信号通路，但 针对 PR 尚未得到应用，因​​为其在 BC 中的作用仍不清楚。我们最近的研究表明 PR 在 BC 中具有重要的免疫调节作用。具体来说，我们的早期研究表明， PR 通过抑制 STAT1/2 来抑制细胞内在干扰素反应。最近，利用转基因PR 模型和原位小鼠 PR+ BC 系，我们证明 PR 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 浸润乳腺肿瘤微环境。这些发现与临床观察结果一致 与其他 BC 相比，HR+ BC 的肿瘤浸润淋巴细胞显着减少，并且 对免疫检查点抑制剂 (ICIs) 的反应较差，例如抗 PD-L1 疗法。因此，我们的过去和现在 研究强烈表明 HR+ BC 免疫抑制是由肿瘤细胞 PR 表达介导的 局部肿瘤微环境（TME）的免疫调节。我们假设治疗靶向 PR 将从根本上改变免疫抑制性乳腺微环境，并提供更强大的功能 ICI 治疗后 HR+ BC 的反应。我们将在以下目标中检验这一假设：1) 通过抗 PD-L1 ICI 确定抗孕激素的抗肿瘤效用，作为引发抗肿瘤免疫的手段 对抗 HR+ 乳腺癌。 2) 确定具有抗 PD-L1 的最佳 Ad-PR 疫苗的抗肿瘤效用 ICI 作为引发针对 HR+ 乳腺癌的抗肿瘤免疫力的一种手段。这些研究我们将确定是否 阻断 PR 可以激活局部抗肿瘤免疫，从而使 HR+ 乳腺癌对治疗敏感 与ICIs。在我们的第一个目标中，我们将确定 PR 信号传导的抗孕激素阻断是否可以逆转局部 PR + 乳腺肿瘤的免疫抑制，以及该方法是否与 ICI 组合具有协同作用。在我们的 第二个目标，我们将利用一种新型 PR 靶向疫苗来刺激针对 PR 的 T 细胞免疫，作为一种新型的 意味着驱动T细胞浸润HR+肿瘤并激活局部抗肿瘤免疫力。 PR 疫苗将 单独进行测试，并与 ICI 联合测试，作为使这些肿瘤对治疗敏感的另一种方法 与ICIs。如果成功，这些研究可以使我们了解 BC 和 PR 免疫调节 允许采用新的免疫学方法治疗 HR+ BC，目前的治疗方法难以治愈该病 免疫治疗干预。