Rescue of Ovarian Tumor Dysregulated CTL by CRH Stress Hormone Antagonism

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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.