Boosting Antitumor Immunity by Blocking Both Tumor and Adipose DDR1

摘要 尽管抗癌免疫治疗在临床上取得了重大突破，但目前的疗效 乳腺癌的免疫疗法并不多见。只有一小部分乳腺癌患者有临床症状 应答；对这些病原体的完全应答是极其罕见的。组织的潜在机制- 乳腺癌的特异性免疫调节机制尚不清楚。此外，像这样的并存 肥胖对乳腺癌患者抗肿瘤免疫的影响更是知之甚少。 盘状结构域受体1(DDR1)是一种具有固有酪氨酸激酶活性的胶原受体。高 乳腺癌中DDR1的表达与患者预后不良和抗肿瘤作用减弱有关 豁免权。我们在乳腺肿瘤中发现了对肿瘤和脂肪DDR1的复杂的促癌作用 微环境。肿瘤DDR1抑制抗肿瘤免疫，而脂肪DDR1是饮食所必需的- 诱导性肥胖、促癌细胞因子的产生和免疫调节。我们的初步数据进一步 提示仅DDR1的胞外区就足以满足其在肿瘤和脂肪中的功能。 细胞，这是以前没有报道过的。因此，我们假设DDR1在乳腺肿瘤中 微环境通过抑制抗肿瘤免疫，促进肥胖，促进肿瘤进展 教唆免疫-脂肪细胞-肿瘤串扰。我们预测阻断非依赖于激酶的DDR1信号可以 增强抗肿瘤免疫和对抗癌免疫疗法的反应，特别是肥胖症患者。至 测试这一假设，在R01的应用中，我们将确定肿瘤DDR1如何抑制抗肿瘤 免疫(目标1)，脂肪DDR1如何促进肥胖相关的癌症进展(目标2)，以及如何 DDR1的免疫抑制功能不依赖于其激酶活性(目标3)。结合使用 在癌症生物学、肿瘤免疫学和临床肿瘤学方面的专业知识，我们的多学科团队很好 来验证我们的新假设。 DDR1在乳腺肿瘤不同细胞亚群中的不同功能 微环境强调了肿瘤-间质相互作用的复杂性。通过研究肿瘤和 脂肪DDR1在这里提出的综合和全面的方式，我们将填补主要空白 关于肿瘤引发的免疫抑制和肥胖相关的共病效应的知识。给定 富含脂肪细胞的肿瘤微环境在乳腺癌和肥胖患者中的作用 乳腺癌，我们建议的研究解决了一个未得到满足的临床需求，并承诺告知 增强乳腺癌患者，特别是肥胖者的抗肿瘤免疫的新策略。 好了！

ABSTRACT Despite significant clinical breakthroughs in anticancer immunotherapy, the efficacy of current immunotherapies in breast cancer is modest. Only a small fraction of breast cancer patients have a clinical response; complete responses to these agents are exceedingly rare. The underlying mechanisms of tissue- specific immune regulation in breast cancer remains to be elucidated. Furthermore, how comorbidities such as obesity influence antitumor immunity in breast cancer is even less understood. Discoidin domain receptor 1 (DDR1) is a collagen receptor with an intrinsic tyrosine kinase activity. High DDR1 expression in breast cancer is associated with poor patient outcomes and attenuated antitumor immunity. We found complex tumor-promoting actions for both tumor and adipose DDR1 in the breast tumor microenvironment. Tumor DDR1 suppresses antitumor immunity, whereas adipose DDR1 is required for diet- induced obesity, tumor-promoting cytokine production, and immune modulation. Our preliminary data further indicate that the shed extracellular domain of DDR1 alone is sufficient for its functions in tumor and adipose cells, which has not previously been reported. We therefore hypothesize that DDR1 in the breast tumor microenvironment promotes tumor progression by dampening antitumor immunity, enabling adiposity, and abetting immune-adipose cell-tumor crosstalk. We predict that blocking kinase-independent DDR1 signals can boost antitumor immunity and response to anticancer immunotherapies, especially in patients with obesity. To test this hypothesis, in this R01 application, we will determine how tumor DDR1 suppresses antitumor immunity (Aim 1), how adipose DDR1 contributes to obesity-associated cancer progression (Aim 2), and how DDR1 carries out its immune-suppressive functions independent of its kinase activity (Aim 3). With combined expertise in cancer biology, tumor immunology, and clinical oncology, our multidisciplinary team is well positioned to validate our novel hypothesis. The fact that DDR1 has distinct functions in different cell compartments of the breast tumor microenvironment underscores the complexity of tumor-stromal interactions. By investigating tumor and adipose DDR1 in an integrative and comprehensive manner as proposed here, we will fill major gaps of knowledge about tumor-initiated immune suppression and obesity-associated comorbid effects. Given the adipocyte-rich tumor microenvironment in breast cancer and the growing numbers of patients with obesity and breast cancer, our proposed studies address an unmet clinical need and promise to inform the development of new strategies to enhance antitumor immunity for breast cancer patients, especially for those with obesity. !