Rewired Metabolism Regulates Vessel Normalization and Immunosuppression

项目摘要 多种特征将肿瘤与正常肿瘤区分开来。其中包括逃脱 免疫监视和异常代谢(糖酵解增加)。这些标志中的每一个都是 经过广泛调查。已经取得了重大进展，特别是最近出现了反 免疫检查点疗法。然而，这些疗法仍然使一小部分患者受益，并取得了成效。 只有少数几种癌症。这反映了不断进化的肿瘤之间的异质性。 促进肿瘤进展的耐药机制。与Sreekumar博士合作，我们的长期目标 是通过整合我们在乳腺癌和其他癌症方面的专业知识来克服治疗耐药性和转移 肿瘤免疫学和新陈代谢领域。在这种情况下，我们的代谢组学数据与后续 研究强调了色氨酸代谢的重要性，特别是犬尿氨酸轴在调节 肿瘤免疫相互作用。在犬尿酸途径酶中，我们鉴定了犬尿氨酸氨基 转移酶(AADAT)在侵袭性基底细胞样瘤中升高，并与不良相关 患者的临床结局与患者对黑色素瘤免疫治疗的反应呈负相关。 AADAT将KYN转化为犬尿酸，过程中使用三氯乙烷的关键成分α酮戊二酸)作为 共底物。我们的初步数据表明，AADAT单手调节能量代谢。 HIF-1α及其受体介导的微环境中肿瘤和免疫细胞的浸润 对血管正常化(VN)的后续影响，这是一种包括改善周细胞附着的动态平衡过程 对内皮细胞，血液灌注量增加，血管通透性降低，从而减少缺氧。 我们早些时候已经证明了在肿瘤中VN和免疫刺激之间的一个新的相互调节环路 促使肿瘤进入具有自我强化的VN和免疫细胞的热状态的微环境 渗透或进入“冷”状态“卡在”发育不良的血管和最低限度渗透的免疫细胞和 对治疗产生抗药性。此外，AADAT耗竭还导致肿瘤细胞中干扰素γ信号的激活， 进一步激活抗肿瘤免疫。基于以上所有，我们假设AADAT促进癌症 刺激免疫抑制和能量代谢的进展和治疗耐药 调节缺氧诱导因子α的表达和活性。我们的具体目标是：目标1：确定机制 AADAT在多种免疫活性乳腺癌和乳腺癌中的免疫抑制作用 黑色素瘤模型。目的2：通过调节瘤内HIF1α来确定AADAT的作用机制 信号轴。目的3确定AADAT的基因缺失或药物抑制是否会使乳房变得敏感 癌症和黑色素瘤免疫检查点阻断疗法(ICBT)。我们研究的影响是标记 AADAT作为免疫和新陈代谢轴的独特调节剂，在肿瘤和周围 微环境，如果得到证实，将揭示侵袭性癌症的单一治疗可操作靶点。

Project Summary Multiple hallmarks distinguish tumors from their normal counterparts. Among these are escape of immune-surveillance and aberrant metabolism (increased glycolysis). Each of these hallmarks has been extensively investigated. Significant progress has been made, especially with the recent emergence of anti- immune checkpoint therapies. However, these therapies still benefit a subset of patients, with efficacy seen only in few cancer types. This reflects the heterogeneity seen between tumors that constantly evolve resistance mechanisms to promote tumor progression. In collaboration with Dr. Sreekumar our long-term goal is to overcome treatment resistance and metastasis in breast and other cancers by integrating our expertise in the areas of tumor immunology and metabolism. In this context, our metabolomics data coupled with follow up studies have highlighted the importance of tryptophan metabolism especially the kynurenine axis in regulating tumor immune interactions. Among the kynureine pathway enzymes, we identified Kynurenine Amino Transferase (AADAT) to be elevated in aggressive basal like tumors and significantly associated with poor clinical outcome in patients and negatively associated with patient’s response to immune therapy in melanoma. AADAT converts KYN to kynurenic acid, in the process using α ketoglutarate, a key component of TCA) as the co-substrate. Our preliminary data demonstrates that AADAT single-handedly regulates energy metabolism in the tumors and immune cell infiltration in the microenvironment potentially mediated via HIF 1α and its consequent effect on vessel normalization (VN), a homeostatic process involving improved pericyte attachment to endothelium, increased blood perfusion, de-creased vessel permeability, and consequently reduced hypoxia. We had earlier demonstrated a novel mutually regulatory loop between VN and immune stimulation in tumor microenvironment that drove the tumor either into a hot” state with self-reinforcing VN and immune cell infiltration or into a “cold” state “stuck” with poorly-developed vessels and minimally infiltrated immune cells and resistant to therapies. Moreover, AADAT depletion also led to activation of IFNγ signaling in cancer cells, further activating anti-tumor immunity. Based on all of the above, we hypothesize that AADAT promotes cancer progression and therapeutic resistance by stimulating immune suppression and energy metabolism by regulating HIF α expression and activity. Our specific aims are: Aim 1: To determine the mechanisms underpinning AADAT’s immunosuppressive functions in various immunocompetent breast cancer and melanoma models. Aim 2: Determine mechanism of action of AADAT by modulating intra-tumoral HIF1α signaling axis. Aim 3 Determine if genetic depletion or pharmacological inhibition of AADAT sensitizes breast cancer and melanoma to immune checkpoint blockade therapies (ICBT). The impact of our study is to mark AADAT as a distinct regulator of immune and metabolism axes, in the tumor and surrounding microenvironment which if proven will reveal a single therapeutically actionable target for aggressive cancers.