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Antiproliferative BTG/Tob proteins interact directly with the CAF1 deadenylase subunit of the CCR4-NOT complex. This binding requires the presence of two conserved motifs, boxA and boxB, characteristic of the BTG/Tob APRO domain. Consistently, these proteins were shown to stimulate mRNA deadenylation and decay in several instances. Two members of the family, BTG1 and BTG2, were reported further to associate with the protein arginine methyltransferase PRMT1 through a motif, boxC, conserved only in this subset of proteins. We recently demonstrated that BTG1 and BTG2 also contact the first RRM domain of the cytoplasmic poly(A) binding protein PABPC1. To decipher the mode of interaction of BTG1 and BTG2 with partners, we performed nuclear magnetic resonance experiments as well as mutational and biochemical analyses. Our data demonstrate that, in the context of an APRO domain, the boxC motif is necessary and sufficient to allow interaction with PABPC1 but, unexpectedly, that it is not required for BTG2 association with PRMT1. We show further that the presence of a boxC motif in an APRO domain endows it with the ability to stimulate deadenylation in cellulo and in vitro. Overall, our results identify the molecular interface allowing BTG1 and BTG2 to activate deadenylation, a process recently shown to be necessary for maintaining T-cell quiescence. [ABSTRACT FROM AUTHOR]

The intracellular peptide pump TAP feeds antigenic peptides for loading onto HLA class I molecules, and its down-modulation is a frequent immune evasion mechanism in human cancers. Two recent papers describe which 'hidden' antigens we might exploit to target these escaped cancer variants by CD8 T cells. These unTAPped peptides are now ready for clinical testing. [ABSTRACT FROM AUTHOR]

Introduction: Checkpoint inhibitor immunotherapy has revolutionized the treatment of many advanced stage cancers. Preexisting immunity is necessary for a response to these agents, which are most effective in inflamed tumors since they principally act by reinforcing preexisting antitumor T-cell responses. An important goal of therapy is to convert the tumor environment from non-inflamed to inflamed in order to facilitate subsequent response to checkpoint inhibitors. Clinical trials are underway to identify checkpoint inhibitor-based combination approaches, which may help to achieve this goal. Areas covered: Anti-PD-1 agents are being assessed in combination with different treatments (e.g. TLR9 agonists, oncolytic peptides, oncolytic vaccines, LAG-3, HDAC inhibitors, GITR, recombinant human interleukin-2) with promising results. PD-1 agents are also being assessed in combination with other locoregional or systemic treatment modalities, including ECT, radiotherapy, chemotherapy, and targeted therapy, with promising results being achieved. Expert commentary: Emerging approaches based on combinations with anti-PD-1 agents seem to offer increased efficacy compared to anti-PD-1 monotherapy. Such combinations also appear to be well tolerated, with safety profiles often comparable to those seen with anti-PD-1 monotherapy. These combination approaches are likely to become an increasing focus of research. There is also the potential for triplet anti-PD-1 combinations. [ABSTRACT FROM AUTHOR]

The article focuses on a study to determine the efficacy and safety of the methotrexate, etoposide, dexamethasone and pegaspargase (MEDA) combination chemotherapy in treating the extranodal natural killer/T-cell lymphoma (ENK/TCL)-associated hemophagocytic lymphohistiocytosis (HLH). Results suggested the successful treatment of ENK/TCL-associated HLH with MEDA regimen.

Introduction: CD40 is a promising therapeutic target for cancer immunotherapy. In patients with advanced solid malignancies, CD40 agonists have demonstrated some anti-tumor activity and a manageable toxicity profile. A 2nd generation of CD40 agonists has now been designed with optimized Fc receptor (FcR) binding based on preclinical evidence suggesting a critical role for FcR engagement in defining the potency of CD40 agonists in vivo. Areas covered: We provide a comprehensive review using PubMed and Google Patent databases on the current clinical status of CD40 agonists, strategies for applying CD40 agonists in cancer therapy, and the preclinical data that supports and is guiding the future development of CD40 agonists. Expert commentary: There is a wealth of preclinical data that provide rationale on several distinct approaches for using CD40 agonists in cancer immunotherapy. This data illustrates the need to strategically combine CD40 agonists with other clinically active treatment regimens in order to realize the full potential of activating CD40 in vivo. Thus, critical to the success of this class of immune-oncology drugs, which have the potential to restore both innate and adaptive immunosurveillance, will be the identification of biomarkers for monitoring and predicting responses as well as informing mechanisms of treatment resistance. [ABSTRACT FROM AUTHOR]

A prerequisite for tumor evolution toward a malignant state is the establishment of cell intrinsic and extrinsic mechanisms of immune suppression (Hanahan and Weinberg, 2000, 2011; Schreiber, Old, and Smyth, 2011). Widespread recruitment of Foxp3+regulatory T cells (TREG) is a prevailing means to dampen antitumor immunity. Advances in the characterization of TREGcell heterogeneity and physiological function of tissue resident TREGcells unfold new possibilities for nontraditional tumor-promoting functions of intratumoral TREGcells. This review will focus on the nonclassical function of TREGcells and their implicancies for cancer biology and treatment. [ABSTRACT FROM AUTHOR]

The significance of lymphocytes functioning to mediate immunological tolerance has garnered increasing appreciation during the last several decades. CD4+ CD25+ α/ β T cells have arguably been the most extensively studied regulatory lymphocyte to date, perhaps owing to the dramatic phenotype observed mice and humans with mutated Foxp3. However, emerging studies suggest that the lineage of regulatory lymphocytes is quite robust. Most notably, while γδ T cells are more traditionally regarded as mediators of cytotoxic function, they are beginning to be regarded as potential negative regulators of immunity. While regulatory γ/δ T cells may possess a degree of transcriptional overlap with ‘classical Tregs’, there remains less clarity in regard to the mechanisms driving the suppressive potential of these cells. In this review, I will discuss the role of Tregs in establishing tolerance in the steady state as well as disease, and how their accumulation and function may be modulated by myeloid cells in the local microenvironment. I will also discuss the necessity to extend our understanding of the regulatory nature of γδ T cells, which may lead to the unearthing of novel paradigms of immunity, perhaps most notably with respect to cancer. [ABSTRACT FROM AUTHOR]

Immunotherapy is becoming an increasingly attractive therapeutic alternative for conventional cancer therapy. In recent years Foxp3+ regulatory T-cells (TR) were identified as the major obstacle to effective cancer immunotherapy. The abundance of these cells in peripheral blood is increased in patients with multiple types of cancer and their prevalence among tumor-infiltrating lymphocytes correlated with poor clinical prognosis. In contrast, removal or inactivation of TR cells led to enhanced anti-tumor immune response and better efficacy of cancer vaccines. This study reports that Bone Morphogenic Protein Receptor 1 α (BMPR1 α, Alk-3) is expressed by activated effector CD4+ and TR cells and modulates functions of both cell types. Bone Morphogenic Proteins (BMPs) belong to the transforming growth factor (TGF)-β family of cytokines that also include TGFβ and activins. BMPs play crucial roles in embryonic development, tissue differentiation and homeostasis, and development of cancer. It was demonstrated that BMPs and activins synergize with TGFβ to regulate thymic T-cell development, maintain TR cells, and control peripheral tolerance. Inactivation of BMPR1 α in T-cells results in impaired thymic and peripheral generation of TR cells. BMPR1 α-deficient activated T-cells produced a higher level of interferon (IFN)- γ than BMPR1 α-sufficient T-cells. Moreover, transplanted B16 melanoma tumors grew smaller in mice lacking expression of BMPR1 α in T-cells and tumors had few infiltrating TR cells and a higher proportion of CD8+ T-cells than wild-type mice. [ABSTRACT FROM AUTHOR]

It has been recently shown that the type I insulin-like growth factor receptor (IGF-IR) contributes significantly to the survival of T lymphoblastic leukemia/lymphoma (T-LBL) cells, and it was therefore suggested that IGF-IR could represent a legitimate therapeutic target in this aggressive disease. Picropodophyllin (PPP) is a potent, selective inhibitor of IGF-IR that is currently used with notable success in clinical trials that include patients with aggressive types of epithelial tumors. In the present study, we tested the effects of PPP on Jurkat and Molt-3 cells; two prototype T-LBL cell lines. Our results demonstrate that PPP efficiently induced apoptotic cell death and cell cycle arrest of these two cells. These effects were attributable to alterations of downstream target proteins. By using proteomic analysis, seven different proteins were found to be affected by PPP treatment of Jurkat cells. These proteins are involved in various aspects of cellular metabolism, cytoskeleton organization and signal transduction pathways. The results suggest that PPP affects multiple signaling molecules and inhibits fundamental pathways that control cell growth and survival. Our study also provides novel evidence that PPP could be potentially utilized for the treatment of aggressive T-LBL. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 68 year old male patient who was admitted to hospital with symptoms of a persistent fever and erythematous rash. A discussion of diagnostic testing which was conducted on the patient, and resulted in him receiving a diagnosis of hypereosinophilic syndrome, is presented. Aggressive T cell leukemia which developed in the patient after his diagnosis of hypereosinophilic syndrome is discussed.

With the emergence of effective immunotherapeutics, which nevertheless harbor the potential for toxicity and are expensive to use, biomarkers are urgently needed for identification of cancer patients who respond to treatment. In this clinical-epidemiological study of 202 cancer patients treated with oncolytic adenoviruses, we address the biomarker value of serum high-mobility group box 1 (HMGB1) protein. Overall survival and imaging responses were studied as primary endpoints and adjusted for confounding factors in two multivariate analyses (Cox and logistic regression). Mechanistic studies included assessment of circulating tumor-specific T-cells by ELISPOT, virus replication by quantitative PCR, and inflammatory cytokines by cytometric bead array. Patients with low HMGB1 baseline levels (below median concentration) showed significantly improved survival (p= 0.008, Log-Rank test) and radiological disease control rate (49.2%vs.30.0%,p= 0.038, χ2test) as compared to high-baseline patients. In multivariate analyses, the low HMGB1 baseline status was a strong prognostic (HR 0.638, 95% CI 0.462–0.881) and the best predictive factor for disease control (OR 2.618, 95% CI 1.004–6.827). Indicative of an immune-mediated mechanism, antitumor T-cell activity in blood and response to immunogenic-transgene coding viruses associated with improved outcome only in HMGB1-low patients. Our results suggest that serum HMGB1 baseline is a useful prognostic and predictive biomarker for oncolytic immunotherapy with adenoviruses, setting the stage for prospective clinical studies. [ABSTRACT FROM PUBLISHER]