Beyond the tumour microenvironment

In contrast to the once dominant tumour-centric view of cancer, increasing attention is now being paid to the tumour microenvironment (TME), generally understood as the elements spatially located in the vicinity of the tumour. Thinking in terms of TME has proven extremely useful, in particular because it has helped identify and comprehend the role of nongenetic and noncell-intrinsic factors in cancer development. Yet some current approaches have led to a TME-centric view, which is no less problematic than the former tumour-centric vision of cancer, insofar as it tends to overlook the role of components located beyond the TME, in the 'tumour organismal environment' (TOE). In this minireview, we highlight the explanatory and therapeutic shortcomings of the TME-centric view and insist on the crucial importance of the TOE in cancer progression

The Multiple Layers of the Tumor Environment

The notion of tumor microenvironment (TME) has been brought to the forefront of recent scientific literature on cancer. However, there is no consensus on how to define and spatially delineate the TME. We propose that the time is ripe to go beyond an all-encompassing list of the components of the TME, and to construct a multilayered view of cancer. We distinguish six layers of environmental interactions with the tumor and show that they are associated with distinct mechanisms, and ultimately with distinct therapeutic approaches

T Follicular Helper Cells in Autoimmune Disorders

T follicular helper (Tfh) cells are a distinct subset of CD4+ T lymphocytes, specialized in B cell help and in regulation of antibody responses. They are required for the generation of germinal center reactions, where selection of high affinity antibody producing B cells and development of memory B cells occur. Owing to the fundamental role of Tfh cells in adaptive immunity, the stringent control of their production and function is critically important, both for the induction of an optimal humoral response against thymus-dependent antigens but also for the prevention of self-reactivity. Indeed, deregulation of Tfh activities can contribute to a pathogenic autoantibody production and can play an important role in the promotion of autoimmune diseases. In the present review, we briefly introduce the molecular factors involved in Tfh cell formation in the context of a normal immune response, as well as markers associated with their identification (transcription factor, surface marker expression, and cytokine production). We then consider in detail the role of Tfh cells in the pathogenesis of a broad range of autoimmune diseases, with a special focus on systemic lupus erythematosus and rheumatoid arthritis, as well as on the other autoimmune/inflammatory disorders. We summarize the observed alterations in Tfh numbers, activation state, and circulating subset distribution during autoimmune and some other inflammatory disorders. In addition, central role of interleukin-21, major cytokine produced by Tfh cells, is discussed, as well as the involvement of follicular regulatory T cells, which share characteristics with both Tfh and regulatory T cells

The antigen presenting potential of Vγ9Vδ2 T-cells during Plasmodium falciparum blood-stage infection.

During Plasmodium falciparum infections, erythrocyte-stage parasites inhibit dendritic cell maturation and function; compromising development of effective anti-malarial adaptive immunity. Human Vγ9Vδ2 T-cells can act in vitro as APCs and induce αβ T-cell activation. However, the relevance of this activity in pathophysiological contexts in vivo has remained elusive. Since Vγ9Vδ2 T-cells are activated during the early immune response against P.falciparum infection, we investigated whether they could contribute to the instruction of adaptive immune responses toward malaria parasites. In P.falciparum-infected patients,Vγ9Vδ2 T-cells presented an increased surface expression of APC-associated markers HLA-DR and CD86. In response to infected red blood cells in vitro, Vγ9Vδ2 T-cells readily up-regulated surface expression of HLA-DR, HLA-ABC, CD40, CD80, CD83 and CD86, induced naive αβ T-cell responses, and cross-presented soluble prototypical protein to antigen-specific CD8+ T-cells. Our findings indicate that P. falciparum parasites induce genuine APC properties in Vγ9Vδ2 T-cells and qualify this subset as an alternative professional APC in malaria patients, which could be harnessed for therapeutic interventions and vaccine design

Targeting self- and foreign antigens to dendritic cells via DC-ASGPR generates IL-10-producing suppressive CD4+ T cells

Dendritic cells (DCs) can initiate and shape host immune responses toward either immunity or tolerance by their effects on antigen-specific CD4(+) T cells. DC-asialoglycoprotein receptor (DC-ASGPR), a lectinlike receptor, is a known scavenger receptor. Here, we report that targeting antigens to human DCs via DC-ASGPR, but not lectin-like oxidized-LDL receptor, Dectin-1, or DC-specific ICAM-3-grabbing nonintegrin favors the generation of antigen-specific suppressive CD4(+) T cells that produce interleukin 10 (IL-10). These findings apply to both self-and foreign antigens, as well as memory and naive CD4(+) T cells. The generation of such IL-10-producing CD4(+) T cells requires p38/extracellular signal-regulated kinase phosphorylation and IL-10 induction in DCs. We further demonstrate that immunization of nonhuman primates with antigens fused to anti-DC-ASGPR monoclonal antibody generates antigen-specific CD4(+) T cells that produce IL-10 in vivo. This study provides a new strategy for the establishment of antigen-specific IL-10-producing suppressive T cells in vivo by targeting whole protein antigens to DCs via DC-ASGPR

Identification de cytokines impliquées dans la génération ou la modulation des fonctions de cellules myéloïdes immunosuppressives associées au cancer

ANGERS-BU Médecine-Pharmacie (490072105) / SudocSudocFranceF