Rescue of Ovarian Tumor Dysregulated CTL by CRH Stress Hormone Antagonism

描述(申请人提供)：卵巢癌，最致命的妇科癌症，在诊断和治疗方面仍然是最有问题的女性癌症。在所有被诊断为卵巢癌的女性中，每年约有2.6万人，只有不到一半的人能存活5年。CD8+T淋巴细胞(CTL)在抗肿瘤免疫反应中起关键作用，它可以侵袭肿瘤部位，提高治疗效果，但这些T细胞不能介导有效的抗肿瘤免疫反应。我们先前研究了良性(非肿瘤)人类女性生殖道的T细胞免疫生物学，并证明当卵巢激素水平较高时，抑制细胞下调CTL杀伤活性，从而导致我们假设子宫内膜CTL的内分泌抑制对于半异基因胎儿的耐受性很重要。在人类卵巢癌中，我们发现肿瘤相关抑制细胞下调了CTL的表达，这表明肿瘤状态下的耐受途径不正确。我们现在建议研究一种可靠的小鼠卵巢癌模型系统，以阐明卵巢肿瘤相关细胞下调CTL的机制，并确定诱导有效抗肿瘤CTL的策略。我们发现，促肾上腺皮质激素释放激素(CRH)受体的拮抗剂antalarmin在体外和体内都能持续地拯救肿瘤相关细胞诱导的CTL死亡。已知Antalarmin通过拮抗胎儿滋养层细胞反击激活的T细胞的能力而诱导妊娠早期啮齿动物胚胎的吸收，证据表明滋养层CRH诱导FasL介导的机制(Makrigiannakis等人)。纳特。免疫系统。2001)。在这里，我们建议进一步发展一种小鼠卵巢肿瘤模型，方法是：1)确定CTL在防止疾病进展中的重要性，以及肿瘤细胞反击CTL的能力；2)证明CRH受体拮抗剂与拯救抗肿瘤CTL的相关性。相关性：内分泌和免疫系统在女性生殖道内相互调节的途径对生殖健康很重要，但人们对此知之甚少。这项研究将阐明卵巢肿瘤与应激激素CRH之间的联系，以及CRH在肿瘤细胞介导的CTL反击中的中心作用，CTL导致抗肿瘤CTL反应无效。

DESCRIPTION (provided by applicant): Ovarian carcinoma, the most lethal gynecologic cancer, remains the most problematic female cancer with respect to diagnosis and treatment. Of all the women diagnosed with ovarian carcinoma, ~ 26,000 every year, less than half will survive 5 years. CD8+ T lymphocytes (CTL), critical for anti-tumor responses, infiltrate the tumor site and associate with improved responses to therapy, yet these T cells fail to mediate effective anti-tumor immunologic responses. We previously studied T cell immunobiology in the benign (non-tumor) human female reproductive tract, and demonstrated that inhibitory cells downregulated CTL killing activity when high levels of ovarian hormones were present, leading us to hypothesize that endocrinologic inhibition of endometrial CTL was important for tolerance of the semi-allogeneic fetus. In human ovarian carcinoma, we found CTL were downregulated by tumor-associated inhibitory cells, suggesting inappropriate tolerizing pathways in the tumor state. We now propose to study a faithful murine ovarian carcinoma model system to elucidate mechanisms by which ovarian tumor-associated cells downregulate CTL, and to define strategies for eliciting effective anti-tumor CTL. We have found that antalarmin, an antagonist to the receptor of corticotropin releasing hormone (CRH, the master stress hormone), consistently rescues CTL from death induced by tumor-associated cells, both in vitro and in vivo. Antalarmin is known to induce the resorption of rodent embryos early in pregnancy via antagonizing the ability of fetal trophoblast cells to counter-attack activated T cells, with evidence of a trophoblast CRH- induced FasL-mediated mechanism (Makrigiannakis et al. Nat. Immunol. 2001). Here, we propose to further develop a murine ovarian tumor model by 1) establishing the importance of CTL in protection against disease progression, and the ability of tumor cells to counter-attack CTL, and 2) demonstrating the relevance of CRH receptor antagonism for rescuing anti-tumor CTL. Relevance: The pathways by which the endocrine and immune systems regulate each other within the female reproductive tract are important for reproductive health but poorly understood. This study will elucidate the link between ovarian tumors and the stress hormone CRH with its proposed central role in tumor cell-mediated counter-attack of CTL that renders anti-tumor CTL responses ineffective.