Dysfunctional T cells can render the immune system unable to eliminate infections and cancer. Therapeutic targeting of the surface receptors that inhibit T cell function has begun to show remarkable ...success in clinical trials. In this Review, we discuss the potential mechanisms of action of the clinical agents that target two of these receptors, programmed cell death protein 1 (PD1) and lymphocyte activation gene 3 protein (LAG3). We also suggest correlative studies that may define the predominant mechanisms of action and identify predictive biomarkers.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
Effector CD8+ T cells are typically thought to be a homogenous group of cytotoxic cells that produce interferon-(IFN) γ. However, recent findings have challenged this notion because multiple subsets ...of CD8+ T cells have been described, each with distinct effector functions and cytotoxic potential. These subsets, referred to as the Tc subsets, have also been detected in tumor microenvironments (TMEs), where they potentially influence the antitumor response and patient outcomes. In this review, we highlight the prevalence and roles of Tc subsets in the TME. We also discuss their therapeutic applications in the context of adoptive immunotherapy to treat cancer.
There are multiple subsets of CD8+ T cells, not all of which have cytotoxic function and produce IFN-γ.A variety of Tc subsets have been detected within the TME and, depending on the subset, can be either positively or negatively correlated with prognosis.In the context of adoptive immunotherapy to treat cancer, the degree of tumor control is greatly influenced by the subset of T cells transferred.
Despite development of new antiviral drugs, viral infections are still a major health problem. The most potent antiviral defense mechanism is the innate production of type I interferon (IFN-I), which ...not only limits virus replication but also promotes antiviral T cell immunity through mechanisms, which remain insufficiently studied. Using the murine lymphocytic choriomeningitis virus model system, we show here that IFN-I signaling on T cells prevented their rapid elimination in vivo. Microarray analyses uncovered that IFN-I triggered the expression of selected inhibitory NK-cell-receptor ligands. Consequently, T cell immunity of IFN-I receptor (IFNAR)-deficient T cells could be restored by NK cell depletion or in NK-cell-deficient hosts (Nfil3–/–). The elimination of Ifnar1–/– T cells was dependent on NK-cell-mediated perforin expression. In summary, we identified IFN-I as a key player regulating the protection of T cells against regulatory NK cell function.
Display omitted
•Ifnar1–/– T cells proliferate in vitro, but not in vivo, suggesting cell interaction•Microarray analyses identify MHC molecules as being regulated by type I interferons•NK cell deficiency rescues expansion and function of IFN-I unresponsive T cells•NK-cell-mediated killing of activated Ifnar1–/– CD8+ T cells depends on perforin
Type I interferons (IFN-I) are important for promoting antiviral T cell immunity, but the mechanisms behind IFN-I action have been unclear. Xu et al. show that IFN-I protects antiviral T cells from regulatory cytotoxic effects of natural killer cells and promotes their expansion and antiviral effector functions.
With the clinical success of CTLA-4 and PD-1 blockade in treating malignancies, there is tremendous interest in finding new ways to augment antitumor responses by targeting other inhibitory ...molecules. In this review, we describe one such molecule. B7-H4, a member of the B7 family of immunoregulatory proteins, inhibits T cell proliferation and cytokine production through ligation of an unknown receptor expressed by activated T cells. Notably, B7-H4 protein expression is observed in a high proportion of patients' tumors across a wide variety of malignancies. This high expression by tumors in combination with its low or absent protein expression in normal tissues makes B7-H4 an attractive immunotherapeutic target. Preclinical investigation into B7-H4-specific chimeric antigen receptor (CAR) T cells, antibody-mediated blockade of B7-H4, and anti-B7-H4 drug conjugates has shown antitumor efficacy in mouse models. The first clinical trials have been completed to assess the safety and efficacy of a B7-H4 fusion protein in ameliorating rheumatoid arthritis.
.
The classical model of hematopoiesis posits the segregation of lymphoid and myeloid lineages as the earliest fate decision. The validity of this model in the mouse has been questioned; however, ...little is known about the lineage potential of human progenitors. Here we provide a comprehensive analysis of the human hematopoietic hierarchy by clonally mapping the developmental potential of seven progenitor classes from neonatal cord blood and adult bone marrow. Human multilymphoid progenitors, identified as a distinct population of Thy-1(neg-lo)CD45RA(+) cells in the CD34(+)CD38(-) stem cell compartment, gave rise to all lymphoid cell types, as well as monocytes, macrophages and dendritic cells, which indicated that these myeloid lineages arise in early lymphoid lineage specification. Thus, as in the mouse, human hematopoiesis does not follow a rigid model of myeloid-lymphoid segregation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The stimulation of Toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS) induces the release of critical proinflammatory cytokines that are necessary to activate potent immune responses. LPS/TLR4 ...signaling has been intensively studied in the past few years. Here we review molecules involved in TLR4-mediated signaling, including players that are involved in the negative regulation of this important pathway.
•Overview of ILC-T cell interactions in inflammation.•Local tissue and tumor microenvironment shape regulatory ILC functions.•Potential role for ILCs in regulating anti-tumor T cell responses.
The ...tumor microenvironment is shaped by interactions between tumor cells, stroma, and immune cells. T cells are a critical component of the immunological anti-tumor response and most immunotherapeutic approaches in cancer aim to augment T cell responses. Recently, innate lymphoid cells (ILCs) have been added to the list of cell populations that influence T cell responses within the tumor microenvironment. ILCs were shown to modulate T cell functions through a variety of mechanisms. However, the impact of ILC and T cell interactions on disease outcome appears to be contextual as their phenotype and function is strongly influenced by the local tissue microenvironment. Here we focus on recent advances in understanding the mechanisms of ILCs in regulating T cell responses in inflammatory diseases and cancer.
Triple-negative breast cancer (TNBC) is a breast cancer subtype that lacks targeted treatment options. The activation of the Notch developmental signaling pathway, which is a feature of TNBC, results ...in the secretion of proinflammatory cytokines and the recruitment of protumoral macrophages to the tumor microenvironment. While the Notch pathway is an obvious therapeutic target, its activity is ubiquitous, and predictably, anti-Notch therapies are burdened with significant on-target side effects. Previously, we discovered that, under conditions of cellular stress commonly found in the tumor microenvironment, the deubiquitinase USP9x forms a multiprotein complex with the pseudokinase tribbles homolog 3 (TRB3) that together activate the Notch pathway. Herein, we provide preclinical studies that support the potential of therapeutic USP9x inhibition to deactivate Notch. Using a murine TNBC model, we show that USP9x knockdown abrogates Notch activation, reducing the production of the proinflammatory cytokines, C-C motif chemokine ligand 2 (CCL2) and interleukin-1 beta (IL-1β). Concomitant with these molecular changes, a reduction in tumor inflammation, the augmentation of antitumor immune response, and the suppression of tumor growth were observed. The pharmacological inhibition of USP9x using G9, a partially selective, small-molecule USP9x inhibitor, reduced Notch activity, remodeled the tumor immune landscape, and reduced tumor growth without associated toxicity. Proving the role of Notch, the ectopic expression of the activated Notch1 intracellular domain rescued G9-induced effects. This work supports the potential of USP9x inhibition to target Notch in metabolically vulnerable tissues like TNBC, while sparing normal Notch-dependent tissues.
PDF
