IL-15/IL-15Rα-secreting bioengineered adipocytes reactivate NK/CD8+ T cells in ovarian and colon cancer ascites

Abstract

Malignant ascites (MA) presents a complex clinical challenge, linked inextricably to poor prognosis, chemoresistance, and metastasis of peritoneal carcinomatosis (PC). However, standard therapeutic approaches for managing or preventing MA secondary to PC remain unavailable. Here we display that a bioengineered adipocyte, encapsulating long-chain fatty acids and concurrently secreting IL-15 and IL-15 receptor α (IL-15Rα), markedly extends the half-life and bioactivity of IL-15. The bioengineered adipocyte consists of an IL-15-P2A-IL-15Rα-T2A-mCherry cDNA sequence stable transfected 3T3-F442A preadipocyte cell line and dcosahexaenoic acid (DHA) are simultaneously encapsulated in the lipid droplets of mature adipocytes, which release it into the MA upon tumor cell-triggered lipolysis. We demonstrate that the bioengineered adipocytes led to specific expansion and activation of NK/CD8⁺ T cells response to the IL-15/IL-15Rα complex in MA, thereby reversing immuno-suppressive phenotype of ascitic immune cells and enabling them to recognize and attack cancer cells. This synergistic therapeutic strategy exhibits therapeutical manipulation of the ascitic immune cells, restores normal immune functioning, and suppresses cancer cell metastasis and tumor growth in ovarian cancer and colon cancer, all while minimizing systemic adverse effects.

Keywords: Adipocytes; CD8(+) T cell; DHA; IL-15/IL-15Rα; Immune therapy; NK cell.