About Me:

Ovarian cancer remains one of the most lethal gynecologic malignancies, with most cases diagnosed at advanced metastatic stages. Although the standard treatment, including surgery and chemotherapy, is effective initially, the benefits are short-lived, resulting in a dismal five-year overall survival rate of 20-30%. This highlights the need for more effective therapeutic strategies, including immunotherapies, which have so far shown very poor efficacy in clinical trials. The presence of tumor-infiltrating lymphocytes, particularly T cells, correlates with improved clinical outcomes, emphasizing the critical role of anti-tumor immune engagement in controlling disease progression and treatment response. However, the molecular mechanisms underlying the exclusion and suppression of immune cells from the tumor microenvironment remain poorly understood. Cytokines mediate intercellular signaling to regulate various aspects of tumor immunity, including immune cell recruitment and activation. Hence, a better understanding of multifaceted cytokine signaling in the tumor microenvironment can identify strategies for improved immunotherapies. To investigate the regulation of T cell infiltration and function in ovarian cancer, we developed a spatial functional genomics screen encompassing 35 genes significantly associated with T cell infiltration in malignant human ovarian tumors, including many cytokine signaling molecules. Our in vivo spatial CRISPR screen identified that the loss of a key cytokine receptor family significantly delays tumor growth. Our spatial as well as single-cell transcriptomics analyses will define how the perturbation of this signaling axis alters the tumor immune microenvironment. We will also test whether this pathway regulates the sensitivity of ovarian tumors to immune checkpoint blockade. Ultimately, this study will uncover key regulators and mechanisms of immune infiltration and function in the ovarian tumor microenvironment with the potential to improve immunotherapy outcomes.