STRESS UNDERMINES IMMUNE STIMULATION: MECHANISMS & BIOLOGICAL SIGNIFICANCE

描述（由申请人提供）：我们最近报道了应激可以阻止免疫刺激剂（ISA）（例如，IL-12）激活细胞介导的免疫（CMI）和控制动物模型中的癌症转移。这种现象可能部分解释了伊萨在癌症患者中的使用相对于动物研究的成功率较低，因为与临床前研究中的动物不同，癌症患者在用ISA治疗时经常经历明显的焦虑和压力。这个问题在癌症患者的短围手术期期间可能特别关键，此时免疫刺激可能潜在地促进患者在肿瘤切除后控制残余肿瘤进展的能力，但有害的心理和生理应激反应被提高。此外，即使在术前实现了成功的免疫刺激，手术也经常导致CMI的严重抑制，使术前免疫刺激无效。为了克服这些障碍，在拟议的研究中，我们的目标是：（i）阐明神经内分泌，免疫，[和肿瘤相关的细胞和分子]机制，通过这些机制，各种压力抑制不同ISA的有益效果;（ii）评估这种现象的生物学意义，使用几种具有临床相关性的癌症转移模型;（iii）设计和测试潜在的预防方法， 规避应激对免疫刺激的这些有害影响的临床适用性;以及 (iv)在原发性肿瘤切除的背景下，组成综合方案，使得能够在应激条件下成功地进行围手术期免疫刺激，以及阻断手术对免疫力和对肿瘤转移的抵抗力的有害影响。为了实现这些目标，我们将使用心理和生理应激范式，并研究[两种]不同的临床批准的ISA的疗效，这是一种正在进行临床研究的新型合成化合物（CpG-C和GLA），可以在围手术期使用，副作用最小。预防手术[本身]的有害影响将建立在我们最近设计的基于COX 2抑制和β-肾上腺素能阻滞的药理学干预基础上，现已批准用于临床试验。待研究的免疫指标将包括最近认识到的对控制肿瘤进展至关重要的免疫机制，包括边缘化肺和边缘化肝免疫细胞、杀伤树突细胞、记忆样NK细胞和抗转移性CMI的几种分子决定因素。将采用小鼠和大鼠的乳腺癌、结肠癌、肺癌和皮肤癌转移模型研究癌症进展。[将分析切除的原发性肿瘤]，并通过基于生物发光的成像重复监测转移性发展。还将在自发转移的原位模型中评估生存率的临床重要结局。拟议的研究将努力阐明应激和免疫刺激在全身和分子水平上相互作用的基本机制，并将这些见解转化为临床可行的治疗方法，可用于接受根治性癌症切除术的癌症患者。

DESCRIPTION (provided by applicant): We recently reported that stress can prevent immuno-stimulatory agents (ISAs) (e.g., IL-12) from activating cell-mediated immunity (CMI) and from controlling cancer metastasis in animal models. This phenomenon may partly account for the lesser success of ISA use in cancer patients relative to animal studies, as unlike animals in preclinical studies, cancer patients often experience marked anxiety and stress while treated with ISAs. This problem may be especially critical during the short peri-operative period in cancer patients, when immune stimulation could potentially promote patients' ability to control residual tumor progression after tumor removal, but deleterious psychological and physiological stress responses are heightened. Additionally, even if successful immune stimulation is achieved pre-operatively, surgery often causes profound suppression of CMI, rendering pre-operative immune stimulation ineffective. To overcome these obstacles, in the proposed study we aim to: (i) elucidate neuroendocrine, immune, [and tumor-related cellular and molecular] mechanisms via which various stressors dampen the beneficial effects of different ISAs; (ii) assess the biological significance of this phenomenon, using several models of cancer metastasis that bear clinical relevance; (iii) devise and test prophylactic approaches of potential clinical applicability to circumvent these deleterious effects of stress on immune stimulation; and (iv) in the context of primary tumor excision, compose integrated regimens that enable both successful peri-operative immune stimulation under stressful conditions, as well as the blockade of the deleterious effects of surgery on immunity and on resistance to tumor metastasis. To achieve these goals we will use psychological and physiological stress paradigms and study the efficacy of [two] different clinically approved ISAs, which are novel synthetic compounds (CpG-C, & GLA) that are under clinical investigation and can be used with minimal adverse effects during the peri-operative period. The prevention of the deleterious effects of surgery [itself] wil build on our recently-devised pharmacological intervention based on a COX2 inhibition and a �-adrenergic blockade, which is now approved for clinical testing. Immune indices to be studied will include recently- recognized immune mechanisms that are critical for controlling tumor progression, including marginating- pulmonary and marginating-hepatic immunocytes, killer dendritic cells, memory-like NK cells, and several molecular determinants of anti-metastatic CMI. Cancer progression will be studied employing models of breast, colon, lung, and skin cancer metastasis in mice and rats. [Excised primary tumors will be analyzed], and metastatic development will be repeatedly monitored by bioluminescence-based imaging. The clinically important outcome of survival rates will also be assessed in orthotopic models of spontaneous metastasis. The proposed studies will strive both to elucidate basic mechanisms of interaction between stress and immune stimulation at the systemic and molecular levels, and to translate these insights into clinically feasible therapeutic approaches that can be used in cancer patients undergoing curative cancer resection.