IL-1R8: A Novel Checkpoint Regulating Anti-Tumor And Anti-Viral Activity Of NK Cells

IL-1R8 is an Interleukin-1 receptor family member that acts as a negative regulator of IL-1 family receptor and Toll-like receptor (TLR) signaling. Both murine and human NK cells express high levels of IL-1R8 but its functional role in this cell type has not been described so far. Natural Killer (NK) cells are innate lymphoid-derived cells and are able to recognize damaged, stressed, viral infected or tumor cells, which express ligands interacting with activating NK cell receptors. The expression of IL1R8 in NK cells prompted us to analyze its potential role in controlling NK cell effector functions.Expression analysis showed that IL-1R8 was acquired during differentiation in human and murine NK cells. IL-1R8 deficiency in the mouse was associated with higher frequency and absolute number of mature NK cells in blood, spleen, bone marrow and liver. Moreover, IL-1R8 deficient NK cells display an increased Interferonγ (IFNγ), Granzyme B and Fas ligand expression and degranulation. IL-18, which is a key regulator of NK cell activities and can be targeted by IL-1R8, was responsible for this phenotype. Indeed, IL-1R8 regulated IL-18 axis during NK cell differentiation and activation and IL-18-dependent activation of mTOR and JNK pathways increased in IL-1R8-deficient NK cells.To assess the role of IL-1R8 in NK cells in pathology, we used models of 3-methylcholanthrene (MCA)-induced lung metastasis, colon cancer-derived liver metastasis and diethylnitrosamine (DEN)-induced hepatocellular carcinoma. The number and dimension of liver and lung metastasis and the liver disease severity were significantly reduced in Il1r8-/- mice. The depletion of NK cells in these models totally abrogated the protection observed in Il1r8-/- mice. Finally, we investigated the role of IL-1R8 in NK cell antiviral activity, in a model of murine cytomegalovirus (MCMV) infection. Il1r8-/- mice showed an improved virus control in the liver and the protection was associated with enhanced NK cell degranulation and IFNγ production. The adoptive transfer of Il1r8-/- NK cells conferred protection in both metastasis and viral infection models. Collectively, these results showed that IL-1R8 played a non-redundant role in the regulation of NK cell development and effector functions by tuning IL-18-dependent activities. IL-1R8 therefore emerges as a novel checkpoint molecule modulating NK cell antitumoral and antiviral potential. Preclinical models showed that the inactivation of IL-1R8 unleashed NK cell effector functions, unveiling IL-1R8 as a potential immunotherapy target in the context of cancer and viral infections

Killing the invaders: NK cell impact in tumors and anti-tumor therapy

Natural Killer cells belong to group 1 innate lymphoid cells, which also includes ILC1s. NK/ILC1s are highly heterogeneous cell types showing distinct phenotypes across tissues and conditions. NK cells have long been described as innate lymphocytes able to directly and rapidly kill tumor cells without antigen-restriction. Different mechanisms were shown to modulate NK cell activation and tumor resistance, mainly based on cytokine stimulation and receptor-ligand interactions, and several strategies have been developed to target NK cells in tumor immunotherapy to promote NK cell function and overcome tumor evasion. The characterization of ILC1 distinct phenotype and function and the specific role in tumors still needs further investigation and will be essential to better understand the impact of innate lymphoid cells in tumors. Here, we review key aspects of NK cell biology that are relevant in tumor immune surveillance, emphasizing the most recent findings in the field. We describe the novel therapeutical strategies that have been developed in tumor immunotherapy targeting NK cells, and we summarize some recent findings related to NK cell/ILC1 transition in tumor models

Inositol phosphatase INPP4B sustains ILC1s and intratumoral NK cells through an AKT-driven pathway

Innate lymphoid cells (ILCs) are a heterogeneous population of lymphocytes that coordinate early immune responses and maintain tissue homeostasis. Type 1 innate immune responses are mediated by natural killer (NK) cells and group 1 ILCs (ILC1s). Despite their shared features, NK cells and ILC1s display profound differences among various tissue microenvironments. Here, we identify the inositol polyphosphatase INPP4B as a hallmark feature of tissue-resident ILC1s and intratumoral NK cells using an scRNA-seq atlas of tissue-associated and circulating NK/ILC1s. Conditional deletion of Inpp4b in ILC1s and NK cells reveals that it is necessary for the homeostasis of tissue-resident ILC1s but not circulating NK cells at steady-state. Inpp4b-deficient cells display increased rates of apoptosis and reduced activation of the prosurvival molecule AKT. Furthermore, expression of Inpp4b by NK/ILC1s is necessary for their presence in the intratumoral environment, and lack of Inpp4b impairs antitumor immunity. These findings highlight INPP4B as a novel regulator of tissue residency and antitumor function in ILC1s and NK cells

IL-1R8 is a checkpoint in NK cells regulating anti-tumour and anti-viral activity

Interleukin-1 receptor 8 (IL-1R8, also known as single immunoglobulin IL-1R-related receptor, SIGIRR, or TIR8) is a member of the IL-1 receptor (ILR) family with distinct structural and functional characteristics, acting as a negative regulator of ILR and Toll-like receptor (TLR) downstream signalling pathways and inflammation. Natural killer (NK) cells are innate lymphoid cells which mediate resistance against pathogens and contribute to the activation and orientation of adaptive immune responses. NK cells mediate resistance against haematopoietic neoplasms but are generally considered to play a minor role in solid tumour carcinogenesis. Here we report that IL-1R8 serves as a checkpoint for NK cell maturation and effector function. Its genetic blockade unleashes NK-cell-mediated resistance to hepatic carcinogenesis, haematogenous liver and lung metastasis, and cytomegalovirus infection

Exploring the impact of TREM2 in tumor-associated macrophages

Tumor-associated macrophages (TAMs) represent a key component of the tumor microenvironment and are generally associated with immunosuppression and poor prognosis. TREM2 is a transmembrane receptor of the immunoglobulin superfamily expressed in myeloid cells. TREM2 has been extensively studied in microglia and neurodegenerative diseases and recently emerged as a marker of pro-tumorigenic macrophages. The accumulation of TREM2-expressing TAMs was reported across numerous cancer patients and tumor models. TREM2 genetic blockade or TREM2 targeting with antibodies resulted in improved tumor control, enhanced response to anti-PD1, and significant changes in the tumor immune landscape. Preclinical studies paved the way for an ongoing clinical trial with a TREM2 depleting antibody and inspired further exploration of TREM2 targeting therapies. Here, we review the current knowledge about the impact of TREM2 in cancer, with an emphasis on the TREM

Priming of Human Resting NK Cells by Autologous M1 Macrophages via the Engagement of IL-1\u3b2, IFN-\u3b2, and IL-15 Pathways

The cross talk between NK cells and macrophages is emerging as a major line of defense against microbial infections and tumors. This study reveals a complex network of soluble mediators and cell-to-cell interactions allowing human classically activated (M1) macrophages, but not resting (M0) or alternatively activated (M2) macrophages, to prime resting autologous NK cells. In this article, we show that M1 increase NK cell cytotoxicity by IL-23 and IFN-\u3b2-dependent upregulation of NKG2D, IL-1\u3b2-dependent upregulation of NKp44, and trans-presentation of IL-15. Moreover, both IFN-\u3b2-dependent cis-presentation of IL-15 on NK cells and engagement of the 2B4-CD48 pathway are used by M1 to trigger NK cell production of IFN-\u3b3. The disclosure of these synergic cellular mechanisms regulating the M1-NK cell cross talk provides novel insights to better understand the role of innate immune responses in the physiopathology of tumor biology and microbial infections

Single-Cell Sequencing of Mouse Heart Immune Infiltrate in Pressure Overload-Driven Heart Failure Reveals Extent of Immune Activation

BACKGROUND: Inflammation is a key component of cardiac disease, with macrophages and T lymphocytes mediating essential roles in the progression to heart failure. Nonetheless, little insight exists on other immune subsets involved in the cardiotoxic response.METHODS: Here, we used single-cell RNA sequencing to map the cardiac immune composition in the standard murine nonischemic, pressure-overload heart failure model. By focusing our analysis on CD45(+) cells, we obtained a higher resolution identification of the immune cell subsets in the heart, at early and late stages of disease and in controls. We then integrated our findings using multiparameter flow cytometry, immunohistochemistry, and tissue clarification immunofluorescence in mouse and human.RESULTS: We found that most major immune cell subpopulations, including macrophages, B cells, T cells and regulatory T cells, dendritic cells, Natural Killer cells, neutrophils, and mast cells are present in both healthy and diseased hearts. Most cell subsets are found within the myocardium, whereas mast cells are found also in the epicardium. Upon induction of pressure overload, immune activation occurs across the entire range of immune cell types. Activation led to upregulation of key subset-specific molecules, such as oncostatin M in proinflammatory macrophages and PD-1 in regulatory T cells, that may help explain clinical findings such as the refractivity of patients with heart failure to anti-tumor necrosis factor therapy and cardiac toxicity during anti-PD-1 cancer immunotherapy, respectively.CONCLUSIONS: Despite the absence of infectious agents or an autoimmune trigger, induction of disease leads to immune activation that involves far more cell types than previously thought, including neutrophils, B cells, Natural Killer cells, and mast cells. This opens up the field of cardioimmunology to further investigation by using toolkits that have already been developed to study the aforementioned immune subsets. The subset-specific molecules that mediate their activation may thus become useful targets for the diagnostics or therapy of heart failure

PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer

PTX3 is an essential component of the humoral arm of innate immunity, playing a nonredundant role in resistance against selected microbes and in the regulation of inflammation. PTX3 activates and regulates the Complement cascade by interacting with C1q and with Factor H. PTX3 deficiency was associated with increased susceptibility to mesenchymal and epithelial carcinogenesis. Increased susceptibility of Ptx3(-/-) mice was associated with enhanced macrophage infiltration, cytokine production, angiogenesis, and Trp53 mutations. Correlative evidence, gene-targeted mice, and pharmacological blocking experiments indicated that PTX3 deficiency resulted in amplification of Complement activation, CCL2 production, and tumor-promoting macrophage recruitment. PTX3 expression was epigenetically regulated in selected human tumors (e.g., leiomyosarcomas and colorectal cancer) by methylation of the promoter region and of a putative enhancer. Thus, PTX3, an effector molecule belonging to the humoral arm of innate immunity, acts as an extrinsic oncosuppressor gene in mouse and man by regulating Complement-dependent, macrophage-sustained, tumor-promoting inflammation