Immunosuppressive Mediators Impair Proinflammatory Innate Lymphoid Cell Function in Human Malignant Melanoma

Abstract

Innate lymphoid cells (ILCs) are a family of immune cells that are emerging as potent orchestrators of immune responses. In cancer, ILCs display both pro- and antitumorigenic functions depending on the nature of the tumor and the involved ILC subset. Little is known about the ILC-tumor crosstalk in human melanoma. Here, we showed that ILC1s were enriched but functionally impaired in cytokine secretion in both PBMCs and tumor-infiltrated lymph nodes of melanoma patients. These findings were confirmed in vivo in murine cutaneous melanoma. Multiple immunosuppressive mechanisms are described in the melanoma microenvironment. Among others, adenosine and kynurenines were shown suppress antitumor immune responses. By exposing ILCs to adenosine and kynurenines we observed a similar shift towards the ILC1 subset distribution and impairment in pro-inflammatory cytokine production to that of patient samples studied ex-vivo. Thus, we hypothesized that the immunosuppressive microenvironment of malignant melanoma might shape ILC sub-populations. Hence, we provide rational for the use of drugs targeting adenosine and kynurenine pathways in melanoma patients.