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In a long-term (up to 11 years) follow-up of nine patients with X-linked severe combined immunodeficiency treated with retroviral insertion of a normal common γ-chain gene into hematopoietic progenitors, seven had durable T-cell reconstitution and long-term survival. B-cell immunity was not corrected. Acute leukemia developed in four patients. In patients without a matched marrow donor, gene therapy may be an option but is associated with serious risks. The cytokine receptor common γ chain, which is encoded by the interleukin-2 receptor subunit gamma ( IL2RG ) gene, is a critical functional component of the receptors for interleukin-2, interleukin-4, interleukin-7, interleukin-9, interleukin-15, and interleukin-21. 1 Naturally occurring mutations in IL2RG are responsible for X-linked severe combined immunodeficiency (SCID-X1) disease. This condition is characterized by the complete lack of T cells and natural killer cells, whereas B cells are present. 2 , 3 Hematopoietic stem-cell transplantation is a lifesaving therapy. Despite associated improvements in the survival rate, however, non−HLA-identical hematopoietic stem-cell transplantation has a number of drawbacks. For example, reconstitution of T-cell function . . .

HSP90 has emerged as an appealing anti-cancer target. However, HSP90 inhibitors (HSP90i) are characterized by limited clinical utility, primarily due to the resistance acquisition via heat shock response (HSR) induction. Understanding the roles of abundantly expressed cytosolic HSP90 isoforms (α and β) in sustaining malignant cells’ growth and the mechanisms of resistance to HSP90i is crucial for exploiting their clinical potential. Utilizing multi-omics approaches, we identified that ablation of the HSP90β isoform induces the overexpression of HSP90α and extracellular-secreted HSP90α (eHSP90α). Notably, we found that the absence of HSP90α causes downregulation of PTPRC (or CD45) expression and restricts in vivo growth of BCR-ABL1+ leukemia cells. Subsequently, chronic long-term exposure to the clinically advanced HSP90i PU-H71 (Zelavespib) led to copy number gain and mutation (p.S164F) of the HSP90AA1 gene, and HSP90α overexpression. In contrast, acquired resistance toward other tested HSP90i (Tanespimycin and Coumermycin A1) was attained by MDR1 efflux pump overexpression. Remarkably, combined CDK7 and HSP90 inhibition display synergistic activity against therapy-resistant BCR-ABL1+ patient leukemia cells via blocking pro-survival HSR and HSP90α overexpression, providing a novel strategy to avoid the emergence of resistance against treatment with HSP90i alone.

Ewing sarcoma (EwS) is an aggressive and highly metastatic bone and soft tissue tumor in pediatric patients and young adults. Cure rates are low when patients present with metastatic or relapsed disease. Therefore, innovative therapy approaches are urgently needed. Cellular- and oncolytic virus-based immunotherapies are on the rise for solid cancers. Here, we assess the combination of EwS tumor-associated antigen CHM1 -specific TCR-transgenic CD8 T cells and the YB-1-driven (i.e. E1A13S-deleted) oncolytic adenovirus XVir-N-31 and in a xenograft mouse model for antitumor activity and immunostimulatory properties. both approaches specifically kill EwS cell lines in a synergistic manner over controls. This effect was confirmed , with increased survival using the combination therapy. Further analyses of immunogenic cell death and antigen presentation confirmed immunostimulatory properties of virus-infected EwS tumor cells. As dendritic cell maturation was also increased by XVir-N-31, we observed superior proliferation of CHM1 -specific TCR-transgenic CD8 T cells only in virus-tested conditions, emphasizing the superior immune-activating potential of XVir-N-31. Our data prove synergistic antitumor effects and superior tumor control in a preclinical xenograft setting. Combination strategies of EwS-redirected T cells and YB-1-driven virotherapy are a highly promising immunotherapeutic approach for EwS and warrant further evaluation in a clinical setting.

BackgroundWhile major advances have been made in improving the quality of life and survival of children with most forms of medulloblastoma (MB), those with MYC-driven tumors (Grp3-MB) still suffer significant morbidity and mortality. There is an urgent need to explore multimodal therapeutic regimens which are effective and safe for children. Large-scale studies have revealed abnormal cancer epigenomes caused by mutations and structural alterations of chromatin modifiers, aberrant DNA methylation, and histone modification signatures. Therefore, targeting epigenetic modifiers for cancer treatment has gained increasing interest, and inhibitors for various epigenetic modulators have been intensively studied in clinical trials. Here, we report a cross-entity, epigenetic drug screen to evaluate therapeutic vulnerabilities in MYC amplified MB, which sensitizes them to macrophage-mediated phagocytosis by targeting the CD47-signal regulatory protein α (SIRPα) innate checkpoint pathway.MethodsWe performed a primary screen including 78 epigenetic inhibitors and a secondary screen including 20 histone deacetylase inhibitors (HDACi) to compare response profiles in atypical teratoid/rhabdoid tumor (AT/RT, n=11), MB (n=14), and glioblastoma (n=14). This unbiased approach revealed the preferential activity of HDACi in MYC-driven MB. Importantly, the class I selective HDACi, CI-994, showed significant cell viability reduction mediated by induction of apoptosis in MYC-driven MB, with little-to-no activity in non-MYC-driven MB, AT/RT, and glioblastoma in vitro. We tested the combinatorial effect of targeting class I HDACs and the CD47-SIRPa phagocytosis checkpoint pathway using in vitro phagocytosis assays and in vivo orthotopic xenograft models.ResultsCI-994 displayed antitumoral effects at the primary site and the metastatic compartment in two orthotopic mouse models of MYC-driven MB. Furthermore, RNA sequencing revealed nuclear factor-kB (NF-κB) pathway induction as a response to CI-994 treatment, followed by transglutaminase 2 (TGM2) expression, which enhanced inflammatory cytokine secretion. We further show interferon-γ release and cell surface expression of engulfment (‘eat-me’) signals (such as calreticulin). Finally, combining CI-994 treatment with an anti-CD47 mAb targeting the CD47-SIRPα phagocytosis checkpoint enhanced in vitro phagocytosis and survival in tumor-bearing mice.ConclusionTogether, these findings suggest a dynamic relationship between MYC amplification and innate immune suppression in MYC amplified MB and support further investigation of phagocytosis modulation as a strategy to enhance cancer immunotherapy responses.

The prerequisite to prevent childhood B-cell acute lymphoblastic leukemia (B-ALL) is to decipher its etiology. The current model suggests that infection triggers B-ALL development through induction of activation-induced cytidine deaminase (AID; also known as AICDA) in precursor B-cells. This evidence has been largely acquired through the use of ex vivo functional studies. However, whether this mechanism governs native non-transplant B-ALL development is unknown. Here we show that, surprisingly, AID genetic deletion does not affect B-ALL development in Pax5-haploinsufficient mice prone to B-ALL upon natural infection exposure. We next test the effect of premature AID expression from earliest pro-B-cell stages in B-cell transformation. The generation of AID off-target mutagenic activity in precursor B-cells does not promote B-ALL. Likewise, known drivers of human B-ALL are not preferentially targeted by AID. Overall these results suggest that infections promote B-ALL through AID-independent mechanisms, providing evidence for a new model of childhood B-ALL development. Infection or chronic inflammation is a risk factor for childhood B-cell precursor acute lymphoblastic leukemia. Here, the authors show that the DNA editing enzyme AID is expressed in infected B cells but using genetic mouse models show that it does not contribute to leukemia pathogenesis.

Background: Very Low Birth Weight preterm infants are at elevated risk for disrupted brain growth and later neurodevelopmental impairment. Bedside-accessible tools for monitoring cerebral development remain limited. Methods: In this retrospective pilot cohort study, 153 Very Low Birth Weight infants (<32 weeks gestational age and/or <1500 g) from two Level III Neonatal Intensive Care Units underwent serial cranial ultrasound assessments. Total brain volume was estimated using an ellipsoid formula derived from standardized imaging planes. Growth trajectories were analysed via linear mixed-effects modelling. Associations with clinical predictors—including invasive ventilation, sepsis, and somatic growth—were evaluated. Results: A total of 976 brain volume measurements were collected. Median cerebral volume increased from 164 cm3 to 275 cm3 across the hospital stay, corresponding to a median growth rate of 2.3 cm3/day (95% CI: 1.5–3.1). Duration of invasive mechanical ventilation was associated with reduced cerebral growth (p < 0.01, R2 = 0.26). Cerebral volume growth showed a weak but statistically significant correlation with head circumference percentile progression (p < 0.05, ρ = 0.16). Conclusions: Sonographic brain volumetry is a feasible and non-invasive method for tracking cerebral development in Very Low Birth Weight infants. These findings confirm significant associations between cerebral growth and head growth and identify prolonged invasive ventilation as a risk factor for impaired cerebral development.

Pediatric sarcomas, including osteosarcoma (OS), Ewing sarcoma (EwS) and rhabdomyosarcoma (RMS) carry low somatic mutational burden and low MHC-I expression, posing a challenge for T cell therapies. Our previous study showed that mediators of monocyte maturation sensitized the EwS cell line A673 to lysis by HLA-A*02:01/CHM1 -specific allorestricted T cell receptor (TCR) transgenic CD8 T cells (CHM1 CD8 T cells). In this study, we tested a panel of monocyte maturation cytokines for their ability to upregulate immunogenic cell surface markers on OS, EwS and RMS cell lines, using flow cytometry. xCELLigence, SRB and ELISpot assays were used to assess whether TNF pretreatment increases CD8 T cell cytotoxicity. We observed that TNF and IL-1β upregulated MHC class I, ICAM-1 as well as CD83 and PD-L1 on the surface of pediatric sarcoma cell lines, while IL-4, GM-CSF, IL-6 and PGE failed to induce respective effects. Although pretreatment of pediatric sarcoma cell lines with TNF did not improve unspecific peripheral blood mononuclear cells (PBMCs) cytotoxicity, TNF enhanced specific lysis of 1/3 HLA-A2 EwS cell lines by CHM1 CD8 T cells depending on MHC-I expression and ICAM-1 upregulation. Our study supports utilization of TNF or TNF-inducing regimens for upregulation of MHC-I and costimulatory surface molecules on pediatric sarcoma cells and for enhancing recognition of responsive HLA-A2 EwS tumor cells by antigen-specific CD8 T cells.

TNF family members and their receptors contribute to increased gene expression for inflammatory processes and intracellular cascades leading to programmed cell death, both via activation of NF-κB. TNF receptor (TNFR)-associated factors (TRAFs) are cytoplasmic adaptor proteins binding to various receptors of the TNFR family. In an attempt to delineate the role of individual TRAFs, we compared NF-κB activation by CD40wtand CD40 mutants with different TRAF recruitment patterns. Recognized only recently, NF-κB signaling occurs at least via two different pathways. Each pathway results in nuclear translocation of two different Reldimers, the canonical p50/RelA and the noncanonical p52/RelB. Here, we show that via TRAF6, CD40 mediates only the activation of the canonical NF-κB pathway. Via TRAF2/5, CD40 activates both the canonical and the noncanonical NF-κB pathways. We observed that TRAF3 specifically blocked the NF-κB activation via TRAF2/5. This inhibitory effect of TRAF3 depends on the presence of an intact zinc finger domain. Paradoxically, suppression of TRAF2/5-mediated NF-κB activation by TRAF3 resulted in enhanced transcriptional activity of TRAF6-mediated canonical NF-κB emanating from CD40. We also observed that 12 TNFR family members (p75TNFR, LTβR, RANK, HVEM, CD40, CD30, CD27, 4- 1BB, GITR, BCMA, OX40, and TACI) are each capable of activating the alternative NF-κB pathway and conclude that TRAF3 serves as a negative regulator of this pathway for all tested receptors.