Natural killer cell and type 1 innate lymphoid cell dichotomy : development and anti-tumoral functions

Les cellules Natural Killer (NK) sont des cellules lymphoïdes innées cytotoxiques, découvertes il y a 45 ans. La complexité de leur étude a été renforcée par la découverte récente des cellules lymphoïdes innées de type 1 (ILC1). Les ILC1 partagent de nombreuses caractéristiques avec les cellules NK et jusqu’à récemment, la majorité des études portant sur les cellules NK intégraient les deux populations. Nous nous sommes attelés à revisiter certaines observations faites sur les cellules NK à la lumière de cette dichotomie cellules NK-ILC1. Nous nous sommes d'abord intéressés aux fonctions de ces cellules en contexte tumoral. Les cellules NK ont été en premier lieu découvertes pour leur capacité à tuer les cellules tumorales in vitro et in vivo. Mais peu d’études ont été menées pour déterminer leur rôle dans le processus d’immunosurveillance tumorale. Grâce à un modèle de tumorigenèse primaire utilisant un carcinogène chimique, nous montrons que les cellules NK et les ILC1 ne jouent pas un rôle prépondérant lors du développement de tumeurs primaires. Néanmoins, ce projet nous a permis de caractériser leurs implications dans l’élimination de tumeurs transplantables. Nous avons pu observer que contrairement au rôle anti-tumoral des cellules NK, les ILC1 posséderaient une activité inhibitrice de la réponse immunitaire anti-tumorale. Nous nous sommes aussi intéressés au développement des ILC1. Les cellules NK et les ILC1 sont issues de lignages distincts mais l’embranchement développemental les séparant est encore inconnu à ce jour. Nous avons pu mettre en évidence un développement extramédullaire dépendant de l'IFN-γ des ILC1 hépatiques à partir de progéniteurs locaux.Natural Killer (NK) cells are cytotoxic innate lymphoid cells discovered 45 years ago. Numerous studies have demonstrated their roles in the defense against pathogens and in the anti-tumor immune response. Consistent with their diversity of functions, NK cells are now recognized as a heterogeneous population. Yet, the recent discovery of type 1 innate lymphoid cells (ILC1) drastically increased the complexity of their study. ILC1 share numerous features with NK cells and until recently, the majority of NK cell studies targeted both populations. Here, we are revisiting some observations made about NK cells through this newly NK cell-ILC1 dichotomy. First, we examined their functions in a tumoral context. NK cells were discovered for their ability to kill tumor cells in vitro and in vivo. But, few studies addressed their role in the tumor immunosurveillance process. Using a chemical carcinogen-induced primary tumor model, we showed that NK cells and ILC1 do not play a critical role during the development of primary tumors. Nonetheless, this project allowed us to characterize their contribution in the elimination of transplantable tumors. Opposed to the anti-tumor role of NK cells, intratumoral ILC1 seem to have an inhibitory action on the anti-tumor immune response. In parallel, we also studied the development of liver-resident ILC1. NK cells and ILC1 belong to two distinct cell lineages but their developmental trajectories remain largely unknown. We discovered that liver ILC1 are generated from tissue-resident progenitors distinct from bone marrow-derived hematopoietic stem cells. We also showed that this process relies of the production of IFN-γ by the ILC1 themselves

Natural killer cell immunotherapies against cancer: checkpoint inhibitors and more

International audienceAfter many years of research, recent advances have shed new light on the role of the immune system in advanced-stage cancer. Various types of immune cells may be useful for therapeutic purposes, along with chemical molecules and engineered monoclonal antibodies. The immune effectors suitable for manipulation for adoptive transfer or drug targeting in vivo include natural killer (NK) cells. These cells are of particular interest because they are tightly regulated by an array of inhibitory and activating receptors, enabling them to kill tumor cells while sparing normal cells. New therapeutic antibodies blocking the interactions of inhibitory receptors (immune checkpoint inhibitors, ICI) with their ligands have been developed and can potentiate NK cell functions in vivo

Minute virus of mice shows oncolytic activity against pancreatic cancer cells exhibiting a mesenchymal phenotype

International audiencePancreatic cancer will soon become the second cause of death by cancer in Western countries. The main barrier to increase the survival of patients with this disease requires the development of novel and efficient therapeutic strategies that better consider tumor biology. In this context, oncolytic viruses emerge as promising therapeutics. Among them, the fibrotropic minute virus of mice prototype (MVMp) preferentially infects migrating and undifferentiated cells that highly resemble poorly differentiated, basal-like pancreatic tumors showing the worst clinical outcome. We report here that MVMp specifically infects, replicates in, and kills pancreatic cancer cells from murine and human origin with a mesenchymal, basal-like profile, while sparing cancer cells with an epithelial phenotype. Remarkably, MVMp infection, at a dose that does not provoke tumor growth inhibition in athymic mice, shows significant antitumoral effect in immune-competent models; extended mouse survival; and promoted the massive infiltration of tumors by innate, myeloid, and cytotoxic T cells that exhibit a less terminally exhausted phenotype. Collectively, we demonstrate herein for the first time that MVMp is specific and oncolytic for pancreatic tumors with mesenchymal, basal-like profile, paving the way for precisionmedicine opportunities for the management of the most aggressive and lethal form of this disease.</div

Research data supporting publication - title to be confirmed.

Microarray analysis of sorted, previously transferred GFP+ Th1 cells from NOD mice treated with either control antibody (NT) or aglycosyl anti-CD3 (T).This work was supported by the ERC and NC3R [grant numbers NC/M001083/1 and health-f5-2009-241883]

Type 1 Innate Lymphoid Cells Limit the Antitumoral Immune Response

International audienceNatural 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

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

International audienceThe 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 Lin − Sca-1 + Mac-1 + hematopoietic stem cells derived from the fetal liver. This population includes Lin − CD122 + CD49a + 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

Natural-Killer-like B Cells Display the Phenotypic and Functional Characteristics of Conventional B Cells

International audienc