Restoration of natural killer cell antimetastatic activity by IL12 and checkpoint blockade

Immune checkpoint therapies target tumor antigen-specific T cells, but less is known about their effects on natural killer (NK) cells, which help control metastasis. In studying the development of lung metastases, we found that NK cells lose their cytotoxic capacity and acquire a molecular signature defined by the expression of coinhibitory receptors. In an effort to overcome this suppressive mechanism, we evaluated NK cell responses to the immunostimulatory cytokine IL12. Exposure to IL12 rescued the cytotoxicity of NK cells but also led to the emergence of an immature NK cell population that expressed high levels of the coinhibitory molecules PD-1, Lag-3, and TIGIT, thereby limiting NK cell-mediated control of pulmonary metastases. Notably, checkpoint blockade therapy synergized with IL12 to fully enable tumor control by NK cells, demonstrating that checkpoint blockers are not only applicable to enhance T cell-mediated immunotherapy, but also to restore the tumor-suppressive capacity of NK cell

Interleukin-12 bypasses common gamma-chain signalling in emergency natural killer cell lymphopoiesis

Differentiation and homeostasis of natural killer (NK) cells relies on common gamma-chain (γc)-dependent cytokines, in particular IL-15. Consequently, NK cells do not develop in mice with targeted γc deletion. Herein we identify an alternative pathway of NK-cell development driven by the proinflammatory cytokine IL-12, which can occur independently of γc-signalling. In response to viral infection or upon exogenous administration, IL-12 is sufficient to elicit the emergence of a population of CD122+CD49b+ cells by targeting NK-cell precursors (NKPs) in the bone marrow (BM). We confirm the NK-cell identity of these cells by transcriptome-wide analyses and their ability to eliminate tumour cells. Rather than using the conventional pathway of NK-cell development, IL-12-driven CD122+CD49b+ cells remain confined to a NK1.1lowNKp46low stage, but differentiate into NK1.1+NKp46+ cells in the presence of γc-cytokines. Our data reveal an IL-12-driven hard-wired pathway of emergency NK-cell lymphopoiesis bypassing steady-state γc-signalling

CSF1R-dependent myeloid cells are required for NK‑mediated control of metastasis

Myeloid leukocytes are essentially involved in both tumor progression and control. We show that neo-adjuvant treatment of mice with an inhibitor of CSF1 receptor (CSF1R), a drug that is used to deplete tumor-associated macrophages, unexpectedly promoted metastasis. CSF1R blockade indirectly diminished the number of NK cells due to a paucity of myeloid cells that provide the survival factor IL-15 to NK cells. Reduction of the number of NK cells resulted in increased seeding of metastatic tumor cells to the lungs but did not impact on progression of established metastases. Supplementation of mice treated with CSF1R-inhibitor with IL-15 restored numbers of NK cells and diminished metastasis. Our data suggest that CSF1R blockade should be combined with administration of IL-15 to reduce the risk of metastasis

Tissue microenvironment dictates the fate and tumor-suppressive function of type 3 ILCs

Innate lymphoid cells (ILCs) have been classified into "functional subsets" according to their transcription factor and cytokine profiles. Although cytokines, such as IL-12 and IL-23, have been shown to shape plasticity of ILCs, little is known about how the tissue microenvironment influences the plasticity, phenotype, and function of these cells. Here, we show clearly demarcated tissue specifications of Rorc-dependent ILCs across lymphoid and nonlymphoid organs. Although intestinal Rorc fate map-positive (Rorc(fm+)) ILCs show a clear ILC3 phenotype, lymphoid tissue-derived Rorc(fm+) ILCs acquire an natural killer (NK) cell/ILC1-like phenotype. By adoptively transferring Rorc(fm+) ILCs into recipient mice, we show that ILCs distribute among various organs and phenotypically adapt to the tissue environment they invade. When investigating their functional properties, we found that only lymphoid-tissue resident Rorc(fm+) ILCs can suppress tumor growth, whereas intestinal Rorc(fm-) ILC1s or NK cells fail to inhibit tumor progression. We thus propose that the tissue microenvironment, combined with ontogeny, provides the specific function, whereas the phenotype is insufficient to predict the functional properties of ILCs