Rescue of Ovarian Tumor Dysregulated CTL by CRH Stress Hormone Antagonism

描述（申请人提供）：卵巢癌是最致命的妇科癌症，在诊断和治疗方面仍然是最困难的女性癌症。在所有被诊断患有卵巢癌的女性中，每年约有26,000人，不到一半的人能存活5年。CD8+ T淋巴细胞（CTL）对抗肿瘤反应至关重要，浸润肿瘤部位并与改善治疗反应有关，但这些T细胞不能介导有效的抗肿瘤免疫反应。我们之前研究了良性（非肿瘤）人类女性生殖道中的T细胞免疫生物学，并证明当卵巢激素水平高时，抑制性细胞下调CTL杀伤活性，这使我们假设子宫内膜CTL的内分泌抑制对半异体胎儿的耐受性很重要。在人卵巢癌中，我们发现CTL被肿瘤相关抑制细胞下调，提示肿瘤状态下不适当的耐受途径。我们现在建议研究一个忠实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，并确定激发有效抗肿瘤CTL的策略。我们发现，抗肾上腺皮质激素释放激素受体（CRH，主应激激素）的拮抗剂，在体外和体内均能持续拯救CTL，使其免于肿瘤相关细胞诱导的死亡。Antalarmin通过拮抗胎儿滋养细胞对抗活化T细胞的能力，在妊娠早期诱导啮齿动物胚胎的吸收，有证据表明滋养细胞CRH诱导fasl介导的机制（Makrigiannakis等）。免疫学杂志，2001)。在此，我们拟进一步建立小鼠卵巢肿瘤模型，1)确定CTL在预防疾病进展中的重要性，以及肿瘤细胞对CTL的反击能力，2)证明CRH受体拮抗剂与抗肿瘤CTL的相关性。相关性：女性生殖道内内分泌和免疫系统相互调节的途径对生殖健康很重要，但人们对其了解甚少。本研究将阐明卵巢肿瘤与应激激素CRH之间的联系，以及其在肿瘤细胞介导的CTL的反击中所起的中心作用，从而使抗肿瘤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.