Human ILC3 Exert TRAIL-Mediated Cytotoxicity Towards Cancer Cells

Abstract

Group 3 helper Innate Lymphoid Cells (ILC3s) are cytokine-producing lymphocytes that respond to stress signals released during disturbed tissue homeostasis and infection. Upon activation, ILC3s secrete IL-22 and IL-17, and orchestrate immune responses against extracellular pathogens. Their role in cancer remains poorly explored. To determine their anti-cancer effector potential, we co-cultured cytokine-activated human ILC3s with cancer cells of different origins. ILC3s were able to directly respond to tumor cells, resulting in enhanced IFN-γ production. Upon tumor cell encounter, ILC3s maintained expression of the transcription factor RORγt, indicating that ILC3s preserved their identity. ILC3s were able to directly kill both hepatocellular carcinoma and melanoma tumor cells expressing cell-death receptor TRAILR2, through the activation of Caspase-8 in target cells. Moreover, liver-derived cytokine-activated ILC3s also expressed TRAIL and were able to eliminate hepatoblastoma cells. Together, our data reveal that ILC3s can participate in anti-tumor immune response through direct recognition of tumor cells resulting in IFN-γ release and TRAIL-dependent cytotoxicity. Thus, ILC3s might be ancillary players of anti-tumor immunity in tissues, acting as primary responders against transformed or metastasizing cells, which might be further exploited for therapies against cancer.

Immune landscape and immunotherapy of hepatocellular carcinoma: focus on innate and adaptive immune cells

“…ILC3s express RORgt, which is essential for their function [ 136 ]. In an in vitro study, ILC3s exerted cytotoxicity against HCC cells mediated by TRAIL [ 137 ]. However, in a murine HCC model, ILC3s lacking the natural cytotoxicity-triggering receptor (NCR − ILC3s) promoted HCC progression by orchestrating the IL-23/IL-17 axis [ 138 ].…”

The role of group 3 innate lymphoid cell in intestinal disease

“…ILC3s have recently been displayed to respond directly to tumor cells by enhancing the production of IFN-g (156). It was discovered that ILC3 may change into an early NK cell phenotype in response to the stimulation of IL-12 and IL-15, owing mostly to the upregulation of EOMES (68).…”

Targeting Potential of Innate Lymphoid Cells in Melanoma and Other Cancers

“…Human ILC3s can be further divided into two groups based on their expression of NKp44 or NKp46, defined as natural cytotoxicity receptor negative (NCR − ) or NCR + ILC3s [ 29 ]. Although defined as a helper population, ILC3s from both the blood and tissue that have been co-cultured with cells of different cancers have exhibited cytotoxic capabilities, mediated by a TRAIL-TRAILR2 pathway [ 65 ]. With the continuous expression of RORγt, these ILC3s show a cytotoxic phenotype unique from NK cells and ILC1s [ 65 ].…”