Stromal-Immune Interactions Promote Immune Suppression in Intraperitoneal Metastasis of Ovarian Carcinoma

High-grade serous (tubo-ovarian) carcinoma (HGSC) is the most lethal gynecologic malignancy and the most common form of ovarian cancer. Most patients (75%) are diagnosed at advanced disease stages, with widespread peritoneal dissemination leading to a poor prognosis. In this study, we characterized the interactions between fibroblasts and immune cells that facilitate the formation of a hospitable niche in metastatic peritoneal ovarian cancer. Analysis of the dynamic changes in cancer-associated fibroblasts (CAF) and immune cells isolated from patients with HGSC and mouse models revealed transcriptional reprogramming during HGSC progression. Functionally, peritoneal fibroblasts promoted myeloid cell recruitment and T-cell dysfunction. Distinct peritoneal metastatic niches featured reciprocal communication between fibroblasts and T cells. In human HGSC peritoneal metastases, the TIGIT-CD155 immune checkpoint signaling axis was upregulated in T cells and CAFs, respectively, and correlated with worse outcomes. This study implicates CAFs as key modulators of the immune microenvironment in intraperitoneal HGSC metastasis and provides potential avenues for therapeutic intervention of stromal-immune interactions to inhibit the metastatic spread of ovarian carcinoma.

Fibroblast-T cell interactions shape a permissive metastatic niche to support intraperitoneal metastasis of ovarian cancer and offer a promising immunotherapeutic target to interrupt disease progression.