Cytotoxic granzyme C–expressing ILC1s contribute to antitumor immunity and neonatal autoimmunity

Abstract

Innate lymphocytes are integral components of the cellular immune system that can coordinate host defense against a multitude of challenges and trigger immunopathology when dysregulated. Natural killer (NK) cells and innate lymphoid cells (ILCs) are innate immune effectors postulated to functionally mirror conventional cytotoxic T lymphocytes and helper T cells, respectively. Here, we showed that the cytolytic molecule granzyme C was expressed in cells with the phenotype of type 1 ILCs (ILC1s) in mouse liver and salivary gland. Cell fate-mapping and transfer studies revealed that granzyme C–expressing innate lymphocytes could be derived from ILC progenitors and did not interconvert with NK cells, ILC2s, or ILC3s. Granzyme C defined a maturation state of ILC1s. These granzyme C–expressing ILC1s required the transcription factors T-bet and, to a lesser extent, Eomes and support from transforming growth factor–β (TGF-β) signaling for their maintenance in the salivary gland. In a transgenic mouse breast cancer model, depleting ILC1s caused accelerated tumor growth. ILC1s gained granzyme C expression following interleukin-15 (IL-15) stimulation, which enabled perforin-mediated cytotoxicity. Constitutive activation of STAT5, a transcription factor regulated by IL-15, in granzyme C–expressing ILC1s triggered lethal perforin-dependent autoimmunity in neonatal mice. Thus, granzyme C marks a cytotoxic effector state of ILC1s, broadening their function beyond “helper-like” lymphocytes.

NK Cells and Other Cytotoxic Innate Lymphocytes in Colorectal Cancer Progression and Metastasis

“…Thus, further fate-tracing and functional studies are needed to discriminate between ILC1-like NK cells with anti- and pro- tumor potentials. Recently, our group [ 29 ] and others [ 34 , 44 ] have found murine Eomes −/lo ILC1 able to express perforin and granzyme A, B, and C and to kill target cells. Liver granzyme A + ILC1 are sensitive to Hobit deletion [ 30 , 44 ] and can originate from fetal ILC1 [ 107 ] or as a product of ILC3–ILC1 plasticity [ 29 ], but not from NK cells.…”

“…Together with NK cells, innate lymphoid cells (ILCs) have been also found both in tumor biopsies of CRC patients and in mouse models of CRC, playing both pro- and anti-tumor activities [ 22 , 23 , 24 , 25 ]. Added complexity is provided by the identification of ILCs expressing perforin and granzymes able to kill target cells, as well as by evidence in mice showing that NK cells and cytotoxic ILC can limit cancer growth [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. In this review, we provide an overview of the features of NK cells and the expanding spectrum of innate lymphocytes with cytotoxic functions.…”

Localization Matters: Epigenetic Regulation of Natural Killer Cells in Different Tissue Microenvironments

“…Cell-type specific SEs often reflected key functional properties, like the Prf1 -associated SE in cNK cells, which was absent in ILC1 and reflects the cytolytic competence of NK cells vs. ILC1. However, in recent years the dogma of non-cytotoxic ILC1s has been challenged by the findings of highly cytotoxic, granzyme expressing ILC1-like cells and ILC1 ( 84 – 88 ). Similarly, in a different study, investigation of hyper-accessible enhancers in CD56 bright and CD56 dim blood NK cells vs. ie ILC1 and ILC3 depicted a clear separation of cells based on 1) their identity (ILC vs. NK cell) and 2) their cytotoxic potential (ILC3 < CD56 bright < ieILC1 < CD56 dim ) ( 89 ).…”

“…Independent of terminology, the phenotypic and functional conversion described here has been shown to inhibit NK cell anti-tumoral functionality ( 118 ). Conversely, TGF-β was recently demonstrated to be required for the maintenance of granzyme C expressing cytotoxic ILC1 in breast cancer tissues and lack of TGF-β signaling in these cells lead to an accelerated tumor growth ( 88 ). It will thus be intriguing to unravel the epigenetic components of the diverse effects downstream TGF-β in different cellular contexts.…”

Development of Human ILCs and Impact of Unconventional Cytotoxic Subsets in the Pathophysiology of Inflammatory Diseases and Cancer

“…Using the PyMT breast carcinoma model, the authors show that these cells expand and contribute to tumor anti-tumor functions in a TGF-b-dependent manner. If a similar ILC1 subset exists in humans remains to be tested (113).…”