Biomedical subjects

Robert J Wechsler-Reya

Publications and source records attributed to Robert J Wechsler-Reya.

3 recordsLinked to original sources

PubMed2026

Local delivery of interferon restores antigen presentation and sensitizes medulloblastoma to T cell killing.

Medulloblastomas are considered immunologically cold and refractory to immunotherapy. One factor contributing to their low immunogenicity is impaired antigen presentation, which allows tumor cells to evade cytotoxic T cells. Using a syngeneic mouse model of medulloblastoma, we demonstrate that despite low expression of MHC class I on tumor cells, depletion of CD8+ T cells accelerates tumor growth, whereas adoptive transfer of tumor-reactive CD8+ T cells prolongs survival. These antitumor effects rely on T cell-derived interferon gamma (IFNγ), which induces MHC class I on tumor cells and facilitates tumor cell killing by T cells. Importantly, delivering IFNγ directly into tumors via convection-enhanced delivery enhances CD8+ T cell-mediated killing of tumor cells and significantly prolongs survival in tumor-bearing mice. These studies highlight the importance of T cells in controlling brain tumors and the value of IFNγ as an adjuvant for T cell-based immunotherapy.

Animals↗

PubMed2024

Just a spoonful of metformin helps the medicine go down.

Diffuse intrinsic pontine glioma (DIPG) is a devastating brain tumor with a need for novel therapies. So far, monotherapies have failed to prolong survival for these patients, and combinatorial strategies have often shown severe, dose-limiting toxicities. In this issue of the JCI, Duchatel, Jackson, and colleagues address this challenge by introducing a drug combination that mitigates side effects and overcomes resistance. After identifying the PI3K/mTOR pathway as a therapeutic vulnerability, they treated DIPG-bearing mice with paxalisib and saw responses but also observed hyperglycemia as a severe side effect. Combining paxalisib with metformin mitigated this toxicity, but also upregulated protein kinase C (PKC) signaling. To tackle this mechanism of resistance, the authors added the PKC inhibitor enzastaurin to their drug combination and showed that this triple therapy led to improved survival. This approach paves the way for improved outcomes for patients with DIPG and other brain tumors.

Humans↗

PubMed2023

3D genome mapping identifies subgroup-specific chromosome conformations and tumor-dependency genes in ependymoma.

Ependymoma is a tumor of the brain or spinal cord. The two most common and aggressive molecular groups of ependymoma are the supratentorial ZFTA-fusion associated and the posterior fossa ependymoma group A. In both groups, tumors occur mainly in young children and frequently recur after treatment. Although molecular mechanisms underlying these diseases have recently been uncovered, they remain difficult to target and innovative therapeutic approaches are urgently needed. Here, we use genome-wide chromosome conformation capture (Hi-C), complemented with CTCF and H3K27ac ChIP-seq, as well as gene expression and DNA methylation analysis in primary and relapsed ependymoma tumors, to identify chromosomal conformations and regulatory mechanisms associated with aberrant gene expression. In particular, we observe the formation of new topologically associating domains ('neo-TADs') caused by structural variants, group-specific 3D chromatin loops, and the replacement of CTCF insulators by DNA hyper-methylation. Through inhibition experiments, we validate that genes implicated by these 3D genome conformations are essential for the survival of patient-derived ependymoma models in a group-specific manner. Thus, this study extends our ability to reveal tumor-dependency genes by 3D genome conformations even in tumors that lack targetable genetic alterations.

Child↗