A distinct innate lymphoid cell population regulates tumor-associated T cells

Abstract

Antitumor T cells are subject to multiple mechanisms of negative regulation1–3. Recent findings that innate lymphoid cells (ILCs) regulate adaptive T cell responses4–6 led us to examine the regulatory potential of ILCs in the context of cancer. We identified a unique ILC population that inhibits tumor-infiltrating lymphocytes (TILs) from high-grade serous tumors, defined their suppressive capacity in vitro, and performed a comprehensive analysis of their phenotype. Notably, the presence of this CD56+CD3− population in TIL cultures was associated with reduced T cell numbers, and further functional studies demonstrated that this population suppressed TIL expansion and altered TIL cytokine production. Transcriptome analysis and phenotypic characterization determined that regulatory CD56+CD3− cells exhibit low cytotoxic activity, produce IL-22, and have an expression profile that overlaps with those of natural killer (NK) cells and other ILCs. NKp46 was highly expressed by these cells, and addition of anti-NKp46 antibodies to TIL cultures abrogated the ability of these regulatory ILCs to suppress T cell expansion. Notably, the presence of these regulatory ILCs in TIL cultures corresponded with a striking reduction in the time to disease recurrence. These studies demonstrate that a previously uncharacterized ILC population regulates the activity and expansion of tumor-associated T cells.

CRTAM+ NK cells endowed with suppressor properties arise in leukemic bone marrow

“…Overall, we suggest the existence of a novel population of NKreg, with potential suppressive properties for the immune response, similar to what was described in solid tumors . Local microenvironment and unique cellular interactions may provide important signals to shape the properties of NK cells.…”

“…In humans, ligation of TLR9 of adult BM progenitor cells promotes the rapid development of NK cells concomitant to up‐regulation of the IL‐15R receptor, although the existence of an IKDC‐like population has not been reported. In contrast, a population of CD56 + CD3 − innate lymphoid cell with low cytotoxic capacity and production of IL‐22, as well as a suppressor‐like NK cell, characterized by producing IL‐10 and TGF‐β, have been recently found, with its precise identity stills to be determined. The abundance of a similar NK cell type, showing HLA‐G + IL‐10 + TGF‐β + phenotype in PB of patients with breast cancer, has been remarkable, suggesting a potential harmful role in antitumor immunity .…”

Progression or suppression: Two sides of the innate lymphoid cells in cancer

“…Group 3 ILCs produce GM‐CSF, which promotes the macrophage subset differentiation and recruitment, induce immunosuppressive FoxP3 + Treg cells de novo generation in the intestine and might indirectly influence tolerogenic responses to commensal bacteria . Furthermore, a recent study on human ovarian cancer demonstrated a population of IL‐22‐producing ILCs with high expression of EOMES, TBX21, GATA3, RORA and AHR that were difficult to classify as NK cells, ILC2s or ILC3s …”

A primer on recent developments in cancer immunotherapy, with a focus on neoantigen vaccines

“…More recently, a "second touch hypothesis" [39] suggests that the high-level picture for polarization of T cells may not yet be complete. New immune cell subtypes continue to be discovered [40] . As one consequence, mathematical modeling of the immune system is likely to remain a difficult endeavor for some time.…”