Glioblastoma multiforme (GBM), the most aggressive brain cancer, recurs because glioblastoma stem cells (GSCs) are resistant to all standard therapies. We showed that GSCs, but not normal astrocytes, are sensitive to lysis by healthy allogeneic natural killer (NK) cells in vitro. Mass cytometry and single-cell RNA sequencing of primary tumor samples revealed that GBM tumor–infiltrating NK cells acquired an altered phenotype associated with impaired lytic function relative to matched peripheral blood NK cells from patients with GBM or healthy donors. We attributed this immune evasion tactic to direct cell-to-cell contact between GSCs and NK cells via αv integrin–mediated TGF-β activation. Treatment of GSC-engrafted mice with allogeneic NK cells in combination with inhibitors of integrin or TGF-β signaling or with TGFBR2 gene–edited allogeneic NK cells prevented GSC-induced NK cell dysfunction and tumor growth. These findings reveal an important mechanism of NK cell immune evasion by GSCs and suggest the αv integrin/TGF-β axis as a potentially useful therapeutic target in GBM.

Adenovirus is an important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation and there is no established therapy. Cidofovir has in vitro efficacy against adenovirus. We performed a retrospective analysis of 45 patients treated with cidofovir for adenovirus from 10 centers. In total, 16 patients had definite adenovirus disease, 13 probable disease, and 16 asymptomatic infections. A total of 31 (69%) patients were successfully treated with cidofovir, 10 failed, and four were not evaluable owing to early death from other causes. Cidofovir therapy was successful in 10 patients with adenovirus disease, 10 patients with probable disease, and in 10 patients with asymptomatic infections. The overall survival at 28 days and 6 months after initiation of cidofovir therapy was 76 and 46%, respectively. Of the patients, 18 developed toxicity associated with cidofovir: 14 developed renal toxicity and four other types of toxicities. We conclude that cidofovir may be useful against adenovirus after allogeneic hematopoietic stem cell transplantation but additional studies are needed.

Key Points: Novel GM-CSF signaling pathways through IFN-γR/IRF-1 and AKT/mTOR provide monocyte licensing for suppressor function. Only licensed but not fresh Ly-6Chigh murine or human CD14+ monocytes secrete nitric oxide or IDO for T-cell suppression.

CD137 (4‐1BB) is a member of the TNFR‐family with costimulatory function, triggering prosurvival signals in activated T‐cells. Upregulation of CD137 upon stimulation allows identifying and isolating live, human antigen‐specific CD8+ T‐cells of all phenotypes, and therefore provides a comprehensive detection method. Furthermore responses against antigen mixtures can be easily detected, enabling antigen discovery in a stepwise deconvoluting approach. In this article, we will discuss various aspects of this methodology, including potential pitfalls as well as a variety of applications, as illustrated by examples from our laboratory. © 2008 International Society for Advancement of Cytometry

Summary. The risk of mortality in children admitted to the paediatric intensive care unit (PICU) after haematopoietic stem cell transplantation is felt to be very high. Life‐threatening complications leading to PICU admission are due to organ toxicity caused by conditioning regimes and graft‐versus‐host disease (GVHD), systemic infections and other organ dysfunctions. Data collected between October 1998 and December 2001 of paediatric patients undergoing haematopoietic stem cell transplantation and thereafter admitted to the PICU were retrospectively analysed in order to reveal the possible causes and risk factors related to death while in the PICU. Twenty‐six PICU admissions were recorded. We found a mortality rate of 57·7% and a 6‐month survival rate of 23·1%. Univariate analysis identified an oncological paediatric risk of mortality (O‐PRISM) score above 10 points, sustained renal failure and a failed negative fluid balance as significant predictors to non‐survival.