RESUMO
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.
Assuntos
Imunidade Inata , Neoplasias , Animais , Humanos , Células Matadoras Naturais , Tecido Linfoide , Camundongos , Microambiente TumoralRESUMO
After 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.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Imunoterapia/métodos , Células Matadoras Naturais/imunologia , Neoplasias/terapia , Transferência Adotiva , Animais , Receptores Coestimuladores e Inibidores de Linfócitos T/imunologia , Citotoxicidade Imunológica , Engenharia Genética , Humanos , Células Matadoras Naturais/transplante , Neoplasias/imunologiaRESUMO
T cells play a key role in the pathogenesis of type 1 diabetes, and targeting the CD3 component of the T-cell receptor complex provides one therapeutic approach. Anti-CD3 treatment can reverse overt disease in spontaneously diabetic non-obese diabetic mice, an effect proposed to, at least in part, be caused by a selective depletion of pathogenic cells. We have used a transfer model to further investigate the effects of anti-CD3 treatment on green fluorescent protein (GFP)+ islet-specific effector T cells in vivo. The GFP expression allowed us to isolate the known effectors at different time-points during treatment to assess cell presence in various organs as well as gene expression and cytokine production. We find, in this model, that anti-CD3 treatment does not preferentially deplete the transferred effector cells, but instead inhibits their metabolic function and their production of interferon-γ. Programmed cell death protein 1 (PD-1) expression was up-regulated on the effector cells from anti-CD3-treated mice, and diabetes induced through anti-PD-L1 antibody could only be reversed with anti-CD3 antibody if the anti-CD3 treatment lasted beyond the point when the anti-PD-L1 antibody was washed out of the system. This suggests that PD-1/PD-L1 interaction plays an important role in the anti-CD3 antibody mediated protection. Our data demonstrate an additional mechanism by which anti-CD3 therapy can reverse diabetogenesis.
Assuntos
Anticorpos/imunologia , Complexo CD3/imunologia , Inflamação/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Regulação para Cima , Animais , Feminino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Receptor de Morte Celular Programada 1/biossíntese , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologiaRESUMO
Pancreatic 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 precision-medicine opportunities for the management of the most aggressive and lethal form of this disease.
RESUMO
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.
Assuntos
Citotoxicidade Imunológica/imunologia , Linfócitos/imunologia , Sarcoma Experimental/imunologia , Animais , Linhagem Celular Tumoral , Perfilação da Expressão Gênica , Humanos , Imunidade Inata , Células Matadoras Naturais/imunologia , Ativação Linfocitária , Linfócitos do Interstício Tumoral/imunologia , Camundongos , Camundongos Endogâmicos C57BLRESUMO
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 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.
Assuntos
Interferon gama/metabolismo , Fígado/citologia , Fígado/imunologia , Linfócitos/citologia , Linfócitos/imunologia , Animais , Hematopoese Extramedular , Imunidade Inata , Interferon gama/genética , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Células Progenitoras Linfoides/citologia , Células Progenitoras Linfoides/metabolismo , Linfopoese , Camundongos , Receptores de Interferon/genética , Receptores de Interferon/metabolismo , Transdução de Sinais , Proteínas com Domínio T/metabolismo , Receptor de Interferon gamaRESUMO
Immuno-oncology is an emerging field that has revolutionized cancer treatment. Most immunomodulatory strategies focus on enhancing T cell responses, but there has been a recent surge of interest in harnessing the relatively underexplored natural killer (NK) cell compartment for therapeutic interventions. NK cells show cytotoxic activity against diverse tumour cell types, and some of the clinical approaches originally developed to increase T cell cytotoxicity may also activate NK cells. Moreover, increasing numbers of studies have identified novel methods for increasing NK cell antitumour immunity and expanding NK cell populations ex vivo, thereby paving the way for a new generation of anticancer immunotherapies. The role of other innate lymphoid cells (group 1 innate lymphoid cell (ILC1), ILC2 and ILC3 subsets) in tumours is also being actively explored. This Review provides an overview of the field and summarizes current immunotherapeutic approaches for solid tumours and haematological malignancies.
Assuntos
Citocinas/uso terapêutico , Imunoterapia Adotiva/métodos , Células Matadoras Naturais/transplante , Neoplasias , Linfócitos T Citotóxicos/transplante , Humanos , Imunidade Inata/imunologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária , Neoplasias/imunologia , Neoplasias/prevenção & controle , Neoplasias/terapia , Linfócitos T Citotóxicos/imunologiaRESUMO
In Box 1 in the originally published version of this article, three key references referring to mouse and human killer inhibitory receptors were mistakenly deleted during revision of the article. These references have now been added to the corrected version of the article.