Transcriptomic analysis of a phase 1 trial for intraperitoneal monocytes plus IFNs in ovarian cancer reveals support and recruitment of cell-mediated immunity.

BACKGROUND: Ovarian cancer is the most lethal gynecological malignancy and lacks therapeutic options in the recurrent setting. We previously determined the safety and initial clinical activity of intraperitoneal autologous monocytes with interferon gamma and interferon alpha (AMIGA) in women with recurrent, platinum-resistant ovarian cancer, but not all enrolled patients showed benefit, warranting further analysis to understand and improve this therapy. EXPERIMENTAL DESIGN: Bulk RNA sequencing and single-cell RNA sequencing were conducted on circulating immune cells from patients with ovarian cancer treated with AMIGA. Primary human monocytes and T cells were isolated from healthy donors and used in co-cultures with ovarian cancer cell lines to test the effects of AMIGA on T-cell recruitment. RESULTS: Comparing circulating immune cells from long-term responders to non-responders from our clinical trial revealed an increased cell-mediated immune response in long-term responders. T cells in AMIGA-treated patients also upregulated unique, specific T cell receptor-beta chain genes. Bulk RNA-seq of peripheral blood mononuclear cells revealed AMIGA-driven upregulation of CXCL10 and CCL2 mRNA. An increase in these chemokines was consistently reflected in patients' malignant ascites. Finally, in vitro models validated increases in CXCL10 as well as CCL2, and demonstrated that these chemokines exert variable effects on T-cell chemotaxis. CONCLUSIONS: The AMIGA-driven effects on T cell recruitment and upregulation of specific T cell receptor-beta chain genes support the development of future combination therapies of intraperitoneal AMIGA and T cell-based immunotherapies.