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）（如IL-12）激活细胞介导免疫（CMI）和控制动物模型中的癌症转移。这一现象可能部分解释了相对于动物研究，ISA在癌症患者中使用的成功率较低的原因，因为与临床前研究中的动物不同，癌症患者在接受ISA治疗时通常会经历明显的焦虑和压力。在肿瘤患者的短围手术期，这一问题可能尤为关键，此时免疫刺激可能会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会加剧。此外，即使术前免疫刺激成功，手术通常会导致CMI的深度抑制，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，各种应激源抑制不同isa的有益作用；（ii）评估这一现象的生物学意义，使用几种具有临床相关性的癌症转移模型；（iii）设计和试验潜在的预防方法

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.