A plea for end-of-life discussions with patients suffering from Huntington's disease: the role of the physician

Neurological Motor Disorder

Epithelial PD-L2 Expression Marks Barrett's Esophagus and Esophageal Adenocarcinoma

Esophageal adenocarcinoma (EAC) is an increasingly common disease with a dismal 5-year survival rate of 10-15%. In the first systematic evaluation of the PD-1 pathway in EAC, we identify expression of PD-L2 in cancer cells in 51.7% of EACs. Epithelial PD-L1 was expressed on only 2% of cases, though PD-L1(+) immune cells were observed in 18% of EACs. We also evaluated expression in the precursor lesion of EAC, Barrett's Esophagus (BE), which emerges following gastric reflux-induced esophageal inflammation, and found PD-L2 expression in BE but not in non-BE esophagitis. As the progression from squamous esophagitis to BE is accompanied by a transition from a Th1 to Th2 immune response, we hypothesized that the Th2 cytokines IL4/IL13 could contribute to PD-L2 induction. We confirmed that these cytokines can augment PD-L2 expression in EAC cell lines. These results suggest that the inflammatory environment in BE and EAC may contribute to the expression of PD-L2. Furthermore, the potential for PD-1 receptor blockade to be effective in EACs with epithelial PD-L2 or immune cell PD-L1 expression should be evaluated in clinical trials

Epithelial PD-L2 Expression Marks Barrett's Esophagus and Esophageal Adenocarcinoma

Esophageal adenocarcinoma (EAC) is an increasingly common disease with a dismal 5-year survival rate of 10-15%. In the first systematic evaluation of the PD-1 pathway in EAC, we identify expression of PD-L2 in cancer cells in 51.7% of EACs. Epithelial PD-L1 was expressed on only 2% of cases, though PD-L1(+) immune cells were observed in 18% of EACs. We also evaluated expression in the precursor lesion of EAC, Barrett's Esophagus (BE), which emerges following gastric reflux-induced esophageal inflammation, and found PD-L2 expression in BE but not in non-BE esophagitis. As the progression from squamous esophagitis to BE is accompanied by a transition from a Th1 to Th2 immune response, we hypothesized that the Th2 cytokines IL4/IL13 could contribute to PD-L2 induction. We confirmed that these cytokines can augment PD-L2 expression in EAC cell lines. These results suggest that the inflammatory environment in BE and EAC may contribute to the expression of PD-L2. Furthermore, the potential for PD-1 receptor blockade to be effective in EACs with epithelial PD-L2 or immune cell PD-L1 expression should be evaluated in clinical trials

Synergy between PI3K signaling and MYC in Burkitt lymphomagenesis

In Burkitt lymphoma (BL), a germinal center B-cell-derived tumor, the pro-apoptotic properties of c-MYC must be counterbalanced. Predicting that survival signals would be delivered by phosphoinositide-3-kinase (PI3K), a major survival determinant in mature B cells, we indeed found that combining constitutive c-MYC expression and PI3K activity in germinal center B cells of the mouse led to BL-like tumors, which fully phenocopy human BL with regard to histology, surface and other markers, and gene expression profile. The tumors also accumulate tertiary mutational events, some of which are recurrent in the human disease. These results and our finding of recurrent PI3K pathway activation in human BL indicate that deregulated c-MYC and PI3K activity cooperate in BL pathogenesis

TIM-3 : a novel regulatory molecule of alloimmune activation

T cell Ig domain and mucin domain (TIM)-3 has previously been established as a central regulator of Th1 responses and immune tolerance. In this study, we examined its functions in allograft rejection in a murine model of vascularized cardiac transplantation. TIM-3 was constitutively expressed on dendritic cells and natural regulatory T cells (Tregs) but only detected on CD4 +FoxP3- and CD8+ T cells in acutely rejecting graft recipients. A blocking anti-TIM-3 mAb accelerated allograft rejection only in the presence of host CD4+ T cells. Accelerated rejection was accompanied by increased frequencies of alloreactive IFN-\u3b3-, IL-6-, and IL-17-producing splenocytes, enhanced CD8+ cytotoxicity against alloantigen, increased alloantibody production, and a decline in peripheral and intragraft Treg/effector T cell ratio. Enhanced IL-6 production by CD4 + T cells after TIM-3 blockade plays a central role in acceleration of rejection. Using an established alloreactivity TCR transgenic model, blockade of TIM-3 increased allospecific effector T cells, enhanced Th1 and Th17 polarization, and resulted in a decreased frequency of overall number of allospecific Tregs. The latter is due to inhibition in induction of adaptive Tregs rather than prevention of expansion of allospecific natural Tregs. In vitro, targeting TIM-3 did not inhibit nTreg-mediated suppression of Th1 alloreactive cells but increased IL-17 production by effector T cells. In summary, TIM-3 is a key regulatory molecule of alloimmunity through its ability to broadly modulate CD4+ T cell differentiation, thus recalibrating the effector and regulatory arms of the alloimmune response

Immune surveillance and therapy of lymphomas driven by Epstein-Barr-Virus protein LMP1 in a mouse model

B cells infected by Epstein-Barr virus (EBV), a transforming virus endemic in humans, are rapidly cleared by the immune system, but some cells harboring the virus persist for life. Under conditions of immunosuppression, EBV can spread from these cells and cause life-threatening pathologies. We have generated mice expressing the transforming EBV latent membrane protein 1 (LMP1), mimicking a constitutively active CD40 coreceptor, specifically in B cells. Like human EBV-infected cells, LMP1(+) B cells were efficiently eliminated by T cells, and breaking immune surveillance resulted in rapid, fatal lymphoproliferation and lymphomagenesis. The lymphoma cells expressed ligands for a natural killer (NK) cell receptor, NKG2D, and could be targeted by an NKG2D-Fc fusion protein. These experiments indicate a central role for LMP1 in the surveillance and transformation of EBV-infected B cells in vivo, establish a preclinical model for B cell lymphomagenesis in immunosuppressed patients, and validate a new therapeutic approach

HSP90 inhibition overcomes ibrutinib resistance in mantle cell lymphoma.

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib induces responses in 70% of patients with relapsed and refractory mantle cell lymphoma (MCL). Intrinsic resistance can occur through activation of the nonclassical NF-κB pathway and acquired resistance may involve the BTK C481S mutation. Outcomes after ibrutinib failure are dismal, indicating an unmet medical need. We reasoned that newer heat shock protein 90 (HSP90) inhibitors could overcome ibrutinib resistance by targeting multiple oncogenic pathways in MCL. HSP90 inhibition induced the complete degradation of both BTK and IκB kinase α in MCL lines and CD40-dependent B cells, with downstream loss of MAPK and nonclassical NF-κB signaling. A proteome-wide analysis in MCL lines and an MCL patient-derived xenograft identified a restricted set of targets from HSP90 inhibition that were enriched for factors involved in B-cell receptor and JAK/STAT signaling, the nonclassical NF-κB pathway, cell-cycle regulation, and DNA repair. Finally, multiple HSP90 inhibitors potently killed MCL lines in vitro, and the clinical agent AUY922 was active in vivo against both patient-derived and cell-line xenografts. Together, these findings define the HSP90-dependent proteome in MCL. Considering the disappointing clinical activity of HSP90 inhibitors in other contexts, trials in patients with MCL will be essential for defining the efficacy of and mechanisms of resistance after ibrutinib failure