Publications by authors named "Eric Vivier"

279 Publications

Type 1 Innate Lymphoid Cells Limit the Antitumoral Immune Response.

Front Immunol 2021 16;12:768989. Epub 2021 Nov 16.

Aix-Marseille Univ, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Immunologie de Marseille-Luminy (CIML), Marseille, France.

Natural killer (NK) cells are known to be able to kill established tumor cell lines, but important caveats remain regarding their roles in the detection and elimination of developing primary tumors. Using a genetic model of selective ILC1 and NK cell deficiency, we showed that these cells were dispensable for tumor immunosurveillance and immunoediting in the MCA-induced carcinogenesis model. However, we were able to generate primary cell lines derived from MCA-induced tumors with graded sensitivity to NK1.1 cells (including NK cells and ILC1). This differential sensitivity was associated neither with a modulation of intratumoral NK cell frequency, nor the capacity of tumor cells to activate NK cells. Instead, ILC1 infiltration into the tumor was found to be a critical determinant of NK1.1 cell-dependent tumor growth. Finally, bulk tumor RNAseq analysis identified a gene expression signature associated with tumor sensitivity to NK1.1 cells. ILC1 therefore appear to play an active role in inhibiting the antitumoral immune response, prompting to evaluate the differential tumor infiltration of ILC1 and NK cells in patients to optimize the harnessing of immunity in cancer therapies.
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http://dx.doi.org/10.3389/fimmu.2021.768989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8637113PMC
November 2021

NKG2A expression identifies a subset of human Vδ2 T cells exerting the highest antitumor effector functions.

Cell Rep 2021 Oct;37(3):109871

Laboratory of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, 20089 Rozzano, Milan, Italy; Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy. Electronic address:

Human Vδ2 cells are innate-like γδ T effectors performing potent immune surveillance against tumors. The constitutive expression of NKG2A identifies a subset of Vδ2 T cells licensed with an intrinsic hyper-responsiveness against cancer. Indeed, the transcriptomic profiles of NKG2A and NKG2A cells characterize two distinct "intralineages" of Vδ2 T lymphocytes that appear early during development, keep their phenotypes, and show self-renewal capabilities in adult life. The hyper-responsiveness of NKG2A Vδ2 T cells is counterbalanced by the inhibitory signaling delivered by human leukocyte antigen E (HLA-E) expressed on malignant cells as a tumor-escape mechanism. However, either masking or knocking out NKG2A restores the capacity of Vδ2 T cells to exert the highest effector functions even against HLA-E tumors. This is highly relevant in the clinic, as the different degrees of engagement of the NKG2A-HLA-E checkpoint in hepatocellular carcinoma, glioblastoma, and non-small cell lung cancer directly impact patients' overall survival. These findings open avenues for developing combined cellular and immunologic anticancer therapies.
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http://dx.doi.org/10.1016/j.celrep.2021.109871DOI Listing
October 2021

The discovery of innate lymphoid cells.

Authors:
Eric Vivier

Nat Rev Immunol 2021 10;21(10):616

Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, Hôpitaux Universitaires de Marseille, Marseille, France.

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http://dx.doi.org/10.1038/s41577-021-00595-yDOI Listing
October 2021

Single-cell transcriptomic landscape reveals tumor specific innate lymphoid cells associated with colorectal cancer progression.

Cell Rep Med 2021 Aug 27;2(8):100353. Epub 2021 Jul 27.

Shanghai Institute of Immunology, Department of Immunology and Microbiology, and the Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.

Innate lymphoid cells (ILCs) are tissue-resident lymphocytes differing from conventional T lymphocytes in having no antigen-specific receptors. ILCs include natural killer (NK) cells, helper-like ILC1s, ILC2s, and ILC3s, and lymphoid tissue-inducer (LTi) cells. Tumor ILCs are frequently found in various cancers, but their roles in cancer immunity and immunotherapy remain largely unclear. We report here the single-cell characterization of blood and gut helper-like ILC subsets in healthy conditions and in colorectal cancer (CRC). The healthy gut contains ILC1s, ILC3s, and ILC3/NKs, but no ILC2s. Additional tumor-specific ILC1-like and ILC2 subsets were identified in CRC patients. Signaling lymphocytic activation molecule family member 1 (SLAMF1) was found to be selectively expressed on tumor-specific ILCs, and higher levels of SLAMF1 ILCs were observed in the blood of CRC patients. The SLAMF1-high group of CRC patients had a significantly higher survival rate than the SLAMF1-low group, suggesting that SLAMF1 is an anti-tumor biomarker in CRC.
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http://dx.doi.org/10.1016/j.xcrm.2021.100353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385246PMC
August 2021

Tumor Microenvironment-Derived R-spondins Enhance Anti-Tumor Immunity to Suppress Tumor Growth and Sensitize for Immune Checkpoint Blockade Therapy.

Cancer Discov 2021 Jun 30. Epub 2021 Jun 30.

Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center

Natural killer (NK) cells and T cells are key effectors of anti-tumor immune responses and major targets of checkpoint inhibitors. In multiple cancer types, we find that the expression of Wnt signaling potentiator R-spondin genes (e.g. RSPO3) is associated with favorable prognosis and is positively correlated with gene signatures of both NK cells and T cells. While endothelial cells and cancer-associated fibroblasts comprise the R-spondin3-producing cells, NK cells and T cells correspondingly express the R-spondin3 receptor LRG6 within the tumor microenvironment. Exogenous expression or intratumor injection of R-spondin3 in tumors enhanced the infiltration and function of cytotoxic effector cells, which led to tumor regression. NK cells and CD8+ T cells independently and cooperatively contributed to R-spondin3-induced control of distinct tumor types. The effect of R-spondin3 was mediated in part through upregulation of MYC and ribosomal biogenesis. Importantly, R-spondin3 expression enhanced tumor sensitivity to anti-PD1 therapy, thereby highlighting new therapeutic avenues.
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http://dx.doi.org/10.1158/2159-8290.CD-20-0833DOI Listing
June 2021

Combination blockade of KLRG1 and PD-1 promotes immune control of local and disseminated cancers.

Oncoimmunology 2021 06 15;10(1):1933808. Epub 2021 Jun 15.

Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University Alpert Medical School, Providence, Rhode Island, USA.

Checkpoint blockade therapy is effective against many cancers; however, new targets need to be identified to treat patients who do not respond to current treatment or demonstrate immune escape. Here, we showed that blocking the inhibitory receptor Killer cell lectin-like receptor G1 (KLRG1) enhances anti-tumor immunity mediated by NK cells and CD8 T cells. We found that loss of KLRG1 signaling alone significantly decreased melanoma and breast cancer tumor growth in the lungs of mice. In addition, we demonstrated that KLRG1 blockade can synergize with PD-1 checkpoint therapy to increase the therapeutic efficacy compared to either treatment alone. This effect was even observed with tumors that do not respond to PD-1 checkpoint therapy. Double blockade therapy led to significantly decreased tumor size, increased frequency and activation of CD8 T cells, and increased NK cell frequency and maturation in the tumor microenvironment. These findings demonstrate that KLRG1 is a novel checkpoint inhibitor target that affects NK and T cell anti-tumor immunity, both alone and in conjunction with established immunotherapies.
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http://dx.doi.org/10.1080/2162402X.2021.1933808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208121PMC
June 2021

["Immune checkpoint inhibitors in oncology"].

Rev Prat 2021 Apr;71(4):374-379

Centre d'immunologie de Marseille-Luminy, Aix-Marseille Université, CNRS, Inserm, Marseille ; hôpital de La Timone, AP-HM, Marseille immunopole, Marseille ; Innate Pharma, Marseille.

"Immune checkpoint inhibitors in oncology.Cancer immunotherapy has revolutionized oncology. It results from a long history that went along with that of immunology, with its hesitations and failures, and which led to two complementary approaches. One consists in manufacturing cancer-specific monoclonal antibodies or cytotoxic T cells that are injected into patients. The other consists in relieving control mechanisms that prevent normally immune effectors from being pathogenic, and thus, freeing anti-cancer immunity from its constraints. These immune checkpoint inhibitors proved markedly efficient, especially in cancers with a poor prognosis. They opened an unprecedented increase in novel immunotherapeutic approaches and clinical trials."
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April 2021

Natural killer cell engagers in cancer immunotherapy: Next generation of immuno-oncology treatments.

Eur J Immunol 2021 08 18;51(8):1934-1942. Epub 2021 Jun 18.

Innate Pharma, Marseille, France.

Immuno-oncology is revolutionizing the treatment of cancers, by inducing the recognition and elimination of tumor cells by the immune system. Recent advances have focused on generating or unleashing tumor antigen-specific T-cell responses, leading to alternative treatment paradigms for many cancers. Despite these successes, the clinical benefit has been limited to a subset of patients and certain tumor types, highlighting the need for alternative strategies. One innovative approach is to broaden and amplify antitumoral immune responses by targeting innate immunity. Particularly, the aim has been to develop new antibody formats capable of stimulating the antitumor activity of innate immune cells, boosting not only their direct role in tumor elimination, but also their function in eliciting multicellular immune responses ultimately resulting in long-lasting tumor control by adaptive immunity. This review covers the development of a new class of synthetic molecules, natural killer cell engagers (NKCEs), which are built from fragments of monoclonal antibodies (mAbs) and are designed to harness the immune functions of NK cells in cancer. As currently shown in preclinical studies and clinical trials, NKCEs are promising candidates for the next generation of tumor immunotherapies.
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http://dx.doi.org/10.1002/eji.202048953DOI Listing
August 2021

Blockade of the co-inhibitory molecule PD-1 unleashes ILC2-dependent antitumor immunity in melanoma.

Nat Immunol 2021 07 7;22(7):851-864. Epub 2021 Jun 7.

Innate Pharma Research Labs, Marseille, France.

Group 2 innate lymphoid cells (ILC2s) are essential to maintain tissue homeostasis. In cancer, ILC2s can harbor both pro-tumorigenic and anti-tumorigenic functions, but we know little about their underlying mechanisms or whether they could be clinically relevant or targeted to improve patient outcomes. Here, we found that high ILC2 infiltration in human melanoma was associated with a good clinical prognosis. ILC2s are critical producers of the cytokine granulocyte-macrophage colony-stimulating factor, which coordinates the recruitment and activation of eosinophils to enhance antitumor responses. Tumor-infiltrating ILC2s expressed programmed cell death protein-1, which limited their intratumoral accumulation, proliferation and antitumor effector functions. This inhibition could be overcome in vivo by combining interleukin-33-driven ILC2 activation with programmed cell death protein-1 blockade to significantly increase antitumor responses. Together, our results identified ILC2s as a critical immune cell type involved in melanoma immunity and revealed a potential synergistic approach to harness ILC2 function for antitumor immunotherapies.
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http://dx.doi.org/10.1038/s41590-021-00943-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611091PMC
July 2021

Phase I Trial of Prophylactic Donor-Derived IL-2-Activated NK Cell Infusion after Allogeneic Hematopoietic Stem Cell Transplantation from a Matched Sibling Donor.

Cancers (Basel) 2021 May 28;13(11). Epub 2021 May 28.

Centre d'Immunologie de Marseille-Luminy CIML, CNRS, INSERM, Aix Marseille Université, 13009 Marseille, France.

: NK cell-based immunotherapy to prevent relapse after allogeneic transplantation is an appealing strategy because NK cells can provide strong antitumor effect without inducing graft-versus-host disease (GVHD). Thus, we designed a phase-I clinical trial evaluating the safety of a prophylactic donor-derived ex vivo IL-2 activated NK cell (IL-2 NK) infusion after allo-HSCT for patients with hematologic malignancies. : Donor NK cells were purified and cultured ex vivo with IL-2 before infusion, at three dose levels. To identify the maximum tolerated dose was the main objective. In addition, we performed phenotypical and functional characterization of the NK cell therapy product, and longitudinal immune monitoring of NK cell phenotype in patients. : Compared to unstimulated NK cells, IL-2 NK cells expressed higher levels of activating receptors and exhibited increased degranulation and cytokine production in vitro. We treated 16 patients without observing any dose-limiting toxicity. At the last follow up, 11 out of 16 treated patients were alive in complete remission of hematologic malignancies without GVHD features and immunosuppressive treatment. s: Prophylactic donor-derived IL-2 NK cells after allo-HSCT is safe with low incidence of GVHD. Promising survivals and IL-2 NK cell activated phenotype may support a potential clinical efficacy of this strategy.
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http://dx.doi.org/10.3390/cancers13112673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198961PMC
May 2021

Innate lymphoid cell recovery and occurrence of GvHD after hematopoietic stem cell transplantation.

J Leukoc Biol 2021 Apr 13. Epub 2021 Apr 13.

APHM, Hôpital de la Timone, Service d'Immunologie, Marseille-Immunopole, Marseille, France.

Lymphocytes are essential for microbial immunity, tumor surveillance, and tissue homeostasis. However, the in vivo development and function of helper-like innate lymphoid cells (ILCs) in humans remain much less well understood than those of T, B, and NK cells. We monitored hematopoietic stem cell transplantation (HSCT) to determine the kinetics of ILC development in both children and adults. It was found that, unlike NK cells, helper-like ILCs recovered slowly, mirroring the pattern observed for T cells, with normalization achieved at 1 year. The type of graft and the proportion of CD34 cells in the graft did not significantly affect ILC reconstitution. As HSCT is often complicated by acute or chronic graft-versus-host disease (GVHD), the potential role of ILC subsets in maintaining tissue integrity in these conditions was also analyzed. It was found that GVHD was associated with lower levels of activated and gut-homing NKp44 ILCP, consistent with a non-redundant role of this ILC subset in preventing this life-threatening disorder in lymphopenic conditions.
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http://dx.doi.org/10.1002/JLB.5A1019-522RRDOI Listing
April 2021

[Involvement of the complement cascade in severe forms of COVID-19].

Med Sci (Paris) 2021 Apr 9;37(4):333-341. Epub 2021 Apr 9.

Innate Pharma, 117 avenue de Luminy, BP 30191, 13276 Marseille Cedex 9, France - Aix Marseille Université, CNRS, Inserm, CIML, Parc Scientifique et Technologique de Luminy, Case 906, 13288 Marseille Cedex 09, France - Assistance Publique des Hôpitaux de Marseille, Marseille Immunopole, Hôpital de la Timone, 264 rue Saint Pierre, 13385 Marseille Cedex 5, France.

The complement system is an essential component of the innate immune system. Its excessive activation during COVID-19 contributes to cytokine storm, disease-specific endothelial inflammation (endotheliitis) and thrombosis that comes with the disease. Targeted therapies of complement inhibition in COVID-19, in particular blocking the C5a-C5aR1 axis have to be taken into account in the establishment of potential biomarkers and development of therapeutic strategies in the most severe forms of the disease.
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http://dx.doi.org/10.1051/medsci/2021021DOI Listing
April 2021

Liver type 1 innate lymphoid cells develop locally via an interferon-γ-dependent loop.

Science 2021 03;371(6536)

Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.

The pathways that lead to the development of tissue-resident lymphocytes, including liver type 1 innate lymphoid cells (ILC1s), remain unclear. We show here that the adult mouse liver contains LinSca-1Mac-1 hematopoietic stem cells derived from the fetal liver. This population includes LinCD122CD49a progenitors that can generate liver ILC1s but not conventional natural killer cells. Interferon-γ (IFN-γ) production by the liver ILC1s themselves promotes the development of these cells in situ, through effects on their IFN-γR liver progenitors. Thus, an IFN-γ-dependent loop drives liver ILC1 development in situ, highlighting the contribution of extramedullary hematopoiesis to regional immune composition within the liver.
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http://dx.doi.org/10.1126/science.aba4177DOI Listing
March 2021

Complement cascade in severe forms of COVID-19: Recent advances in therapy.

Eur J Immunol 2021 07 10;51(7):1652-1659. Epub 2021 Apr 10.

Innate Pharma Research labs, Marseille, France.

The complement system is an essential component of the innate immune system. The three complement pathways (classical, lectin, alternative) are directly or indirectly activated by the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). In the most severe forms of COVID-19, overactivation of the complement system may contribute to the cytokine storm, endothelial inflammation (endotheliitis) and thrombosis. No antiviral drug has yet been shown to be effective in COVID-19. Therefore, immunotherapies represent a promising therapeutic in the immunopathological phase (following the viral phase) of the disease. Complement blockade, mostly C5a-C5aR axis blockade, may prevent acute respiratory distress syndrome (ARDS) from worsening or progression to death. Clinical trials are underway.
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http://dx.doi.org/10.1002/eji.202048959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250085PMC
July 2021

ILC3s control splenic cDC homeostasis via lymphotoxin signaling.

J Exp Med 2021 05;218(5)

Laboratory of Immunoregulation and Mucosal Immunology, VIB-UGhent Center for Inflammation Research, Ghent, Belgium.

The spleen contains a myriad of conventional dendritic cell (cDC) subsets that protect against systemic pathogen dissemination by bridging antigen detection to the induction of adaptive immunity. How cDC subsets differentiate in the splenic environment is poorly understood. Here, we report that LTα1β2-expressing Rorgt+ ILC3s, together with B cells, control the splenic cDC niche size and the terminal differentiation of Sirpα+CD4+Esam+ cDC2s, independently of the microbiota and of bone marrow pre-cDC output. Whereas the size of the splenic cDC niche depended on lymphotoxin signaling only during a restricted time frame, the homeostasis of Sirpα+CD4+Esam+ cDC2s required continuous lymphotoxin input. This latter property made Sirpα+CD4+Esam+ cDC2s uniquely susceptible to pharmacological interventions with LTβR agonists and antagonists and to ILC reconstitution strategies. Together, our findings demonstrate that LTα1β2-expressing Rorgt+ ILC3s drive splenic cDC differentiation and highlight the critical role of ILC3s as perpetual regulators of lymphoid tissue homeostasis.
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http://dx.doi.org/10.1084/jem.20190835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970251PMC
May 2021

Tumor-Infiltrating Natural Killer Cells.

Cancer Discov 2021 01 4;11(1):34-44. Epub 2020 Dec 4.

Innate Pharma Research Laboratories, Innate Pharma, Marseille, France.

Because of their potent antitumor activity and their proinflammatory role, natural killer (NK) cells are at the forefront of efforts to develop immuno-oncologic treatments. NK cells participate in immune responses to tumors by killing target cells and producing cytokines. However, in the immunosuppressive tumor microenvironment, NK cells become dysfunctional through exposure to inhibitory molecules produced by cancer cells, leading to tumor escape. We provide an overview of what is known about NK tumor infiltration and surveillance and about the mechanisms by which NK cells become dysfunctional. SIGNIFICANCE: The functions of tumor-infiltrating NK cells may be impaired. This review aims to describe the various mechanisms by which tumors alter NK-cell functions.
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http://dx.doi.org/10.1158/2159-8290.CD-20-0655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611243PMC
January 2021

Multidimensional molecular controls defining NK/ILC1 identity in cancers.

Semin Immunol 2021 Feb 1;52:101424. Epub 2020 Dec 1.

Aix Marseille University, CNRS, INSERM, CIML, Marseille, France. Electronic address:

Innate Lymphoid Cells (ILCs) are a recently described heterogeneous population of non-T, non-B lymphocytes. They are highly abundant at mucosal interfaces and, unlike T and B cells, they do not express somatically rearranged antigen-specific receptors. ILCs may be seen as the innate counterparts of T cells, but, major ILC deficiencies in humans appear to be clinically silent in modern conditions of hygiene and medicine, provided that T and B functions are preserved. NK cells are the founder members of this family and were originally classified in group 1 ILCs with ILC1s, due to similarities in cytokine production and development between these two types of cell. The classification of the ILC subsets was subsequently reviewed and five groups were defined on the basis of cytokine production and the discovery of specific transcription factors determining the different lineages. ILCs include NK cells, lymphoid tissue-inducer (LTi) cells and three other main subsets: ILC1s, ILC2s and ILC3s. The nature of distinct ILC1 population in mice and human is not consensual due to the high degree of similarity between ILCs and NK cells and their plastic relationships in some context. In this review, we will discuss the characteristics currently used for the phenotyping of NK cells and ILC1s in mice and humans, in the context of cancers especially, in which inappropriate discrimination between these two cell types can lead to erroneous conclusions regarding the specific impact of their targeting on tumors. Here, we suggest that multidimensional molecular controls, with the co-ordination of ontogeny-related signals, tissue-specific and tumor microenvironment-derived signals, determine the identity of NK cells and ILC1s. All these molecular stratifications contribute to the construction of cell fate for NK cells and ILC1s and account for the difficulties distinguishing between these two groups of cells.
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http://dx.doi.org/10.1016/j.smim.2020.101424DOI Listing
February 2021

Single-cell profiling reveals the trajectories of natural killer cell differentiation in bone marrow and a stress signature induced by acute myeloid leukemia.

Cell Mol Immunol 2021 05 25;18(5):1290-1304. Epub 2020 Nov 25.

Aix Marseille University, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, Marseille, France.

Natural killer (NK) cells are innate cytotoxic lymphoid cells (ILCs) involved in the killing of infected and tumor cells. Among human and mouse NK cells from the spleen and blood, we previously identified by single-cell RNA sequencing (scRNAseq) two similar major subsets, NK1 and NK2. Using the same technology, we report here the identification, by single-cell RNA sequencing (scRNAseq), of three NK cell subpopulations in human bone marrow. Pseudotime analysis identified a subset of resident CD56 NK cells, NK0 cells, as the precursor of both circulating CD56 NK1-like NK cells and CD56 NK2-like NK cells in human bone marrow and spleen under physiological conditions. Transcriptomic profiles of bone marrow NK cells from patients with acute myeloid leukemia (AML) exhibited stress-induced repression of NK cell effector functions, highlighting the profound impact of this disease on NK cell heterogeneity. Bone marrow NK cells from AML patients exhibited reduced levels of CD160, but the CD160 group had a significantly higher survival rate.
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http://dx.doi.org/10.1038/s41423-020-00574-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093261PMC
May 2021

Campylobacter infection promotes IFNγ-dependent intestinal pathology via ILC3 to ILC1 conversion.

Mucosal Immunol 2021 05 19;14(3):703-716. Epub 2020 Nov 19.

Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health San Antonio, San Antonio, TX, USA.

Innate lymphoid cells (ILCs) are a heterogeneous family of immune regulators that protect against mucosal pathogens but can also promote intestinal pathology. Although the plasticity between ILCs populations has been described, the role of mucosal pathogens in inducing ILC conversion leading to intestinal pathology remains unclear. Here we demonstrate that IFNγ-producing ILCs are responsible for promoting intestinal pathology in a mouse model of enterocolitis caused by Campylobacter jejuni, a common human enteric pathogen. Phenotypic analysis revealed a distinct population of IFNγ-producing NK1.1T-betILCs that accumulated in the intestine of C. jejuni-infected mice. Adoptive transfer experiments demonstrated their capacity to promote intestinal pathology. Inactivation of T-bet in NKp46 ILCs ameliorated disease. Transcriptome analysis and cell-fate mapping experiments revealed that IFNγ-producing NK1.1ILCs correspond to ILC1 profile and develop from RORγt progenitors. Collectively, we identified a distinct population of NK1.1ex-ILC3s that promotes intestinal pathology through IFNγ production in response to C. jejuni infection.
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http://dx.doi.org/10.1038/s41385-020-00353-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084871PMC
May 2021

Natural killers or ILC1s? That is the question.

Curr Opin Immunol 2021 02 14;68:48-53. Epub 2020 Oct 14.

Aix Marseille Univ, CNRS, INSERM, CIML, Marseille, France; Assistance Publique des Hôpitaux de Marseille, Hôpital de la Timone, Immunology, Marseille Immunopole, France; Innate Pharma, Marseille, France.

Group 1 innate lymphoid cells (ILCs) comprise the natural killer (NK) cells and ILC1s. Both cells co-exist in peripheral tissues and despite effort to characterize the molecular identity and developmental pathways of ILC1s, their relationship with NK cells remains elusive. ILC1s and NK cells share many common features and analysis of ILC1s in tissues revealed a great heterogeneity and distinct transcriptional requirement of each ILC1 subsets complexifying the organization of this group. Here, we discuss whether ILC1 and NK cells can be considered as distinct lineages based on their origin, location, phenotype or transcriptional regulation. Discrimination of NK cells and ILC1s represent an important challenge to unravel the individual functions of these cells during infection and tumor immunosurveillance.
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http://dx.doi.org/10.1016/j.coi.2020.08.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925336PMC
February 2021

Association of COVID-19 inflammation with activation of the C5a-C5aR1 axis.

Nature 2020 12 29;588(7836):146-150. Epub 2020 Jul 29.

Innate Pharma, Marseilles, France.

Coronavirus disease 2019 (COVID-19) is a disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in a pandemic. The C5a complement factor and its receptor C5aR1 (also known as CD88) have a key role in the initiation and maintenance of several inflammatory responses by recruiting and activating neutrophils and monocytes. Here we provide a longitudinal analysis of immune responses, including phenotypic analyses of immune cells and assessments of the soluble factors that are present in the blood and bronchoalveolar lavage fluid of patients at various stages of COVID-19 severity, including those who were paucisymptomatic or had pneumonia or acute respiratory distress syndrome. The levels of soluble C5a were increased in proportion to the severity of COVID-19 and high expression levels of C5aR1 receptors were found in blood and pulmonary myeloid cells, which supports a role for the C5a-C5aR1 axis in the pathophysiology of acute respiratory distress syndrome. Anti-C5aR1 therapeutic monoclonal antibodies prevented the C5a-mediated recruitment and activation of human myeloid cells, and inhibited acute lung injury in human C5aR1 knock-in mice. These results suggest that blockade of the C5a-C5aR1 axis could be used to limit the infiltration of myeloid cells in damaged organs and prevent the excessive lung inflammation and endothelialitis that are associated with acute respiratory distress syndrome in patients with COVID-19.
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http://dx.doi.org/10.1038/s41586-020-2600-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116884PMC
December 2020

Inflammation-Induced Lactate Leads to Rapid Loss of Hepatic Tissue-Resident NK Cells.

Cell Rep 2020 07;32(1):107855

Division of Biology and Medicine, Department of Molecular Microbiology and Immunology, Brown University Alpert Medical School, Providence, RI 02912, USA. Electronic address:

The liver harbors two main innate lymphoid cell (ILC) populations: conventional NK (cNK) cells and tissue-resident NK (trNK) cells. Using the MCMV model of infection, we find that, in contrast to liver cNK cells, trNK cells initially undergo a contraction phase followed by a recovery phase to homeostatic levels. The contraction is MCMV independent because a similar phenotype is observed following poly(I:C)/CpG or α-GalCer injection. The rapid contraction phase is due to apoptosis, whereas the recovery phase occurs via proliferation in situ. Interestingly, trNK cell apoptosis is not mediated by fratricide and not induced by liver lymphocytes or inflammatory cytokines. Instead, we find that trNK cell apoptosis is the consequence of an increased sensitivity to lactic acid. Mechanistic analysis indicates that trNK cell sensitivity to lactate is linked to impaired mitochondrial function. These findings underscore the distinctive properties of the liver-resident NK cell compartment.
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http://dx.doi.org/10.1016/j.celrep.2020.107855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383148PMC
July 2020

Maternal diesel particle exposure promotes offspring asthma through NK cell-derived granzyme B.

J Clin Invest 2020 08;130(8):4133-4151

Division of Allergy and Clinical Immunology, Department of Medicine, National Jewish Health (NJH), Denver, Colorado, USA.

Mothers living near high-traffic roads before or during pregnancy are more likely to have children with asthma. Mechanisms are unknown. Using a mouse model, here we showed that maternal exposure to diesel exhaust particles (DEP) predisposed offspring to allergic airway disease (AAD, murine counterpart of human asthma) through programming of their NK cells; predisposition to AAD did not develop in DEP pups that lacked NK cells and was induced in normal pups receiving NK cells from WT DEP pups. DEP NK cells expressed GATA3 and cosecreted IL-13 and the killer protease granzyme B in response to allergen challenge. Extracellular granzyme B did not kill, but instead stimulated protease-activated receptor 2 (PAR2) to cooperate with IL-13 in the induction of IL-25 in airway epithelial cells. Through loss-of-function and reconstitution experiments in pups, we showed that NK cells and granzyme B were required for IL-25 induction and activation of the type 2 immune response and that IL-25 mediated NK cell effects on type 2 response and AAD. Finally, experiments using human cord blood and airway epithelial cells suggested that DEP might induce an identical pathway in humans. Collectively, we describe an NK cell-dependent endotype of AAD that emerged in early life as a result of maternal exposure to DEP.
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http://dx.doi.org/10.1172/JCI130324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410053PMC
August 2020

Immuno-Oncology beyond TILs: Unleashing TILCs.

Cancer Cell 2020 04;37(4):428-430

Innate Pharma Research Laboratories, Innate Pharma, Marseille, France; Aix Marseille University, CNRS, INSERM, CIML, Marseille, France; APHM, Hôpital de la Timone, Service d'Immunologie, Marseille-Immunopôle, Marseille, France.

Innate lymphoid cells (ILCs) are detected in multiple tumor types, but their contribution to tumor immunity remains unclear. Moral et al. show that a subset of tumor ILCs (TILCs) may participate in an organ-specific immune response and can be unleashed by PD-1 blockers to sustain tumor-specific T cell responses.
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http://dx.doi.org/10.1016/j.ccell.2020.03.021DOI Listing
April 2020
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