In cancer, immune exhaustion contributes to the immunosuppressive tumor microenvironment. Exhausted immune cells demonstrate poor effector function and sustained expression of certain immunomodulatory receptors, which can be therapeutically targeted. CD244 is a Signaling Lymphocyte Activation Molecule (SLAM) family immunoregulatory receptor found on many immune cell types—including NK cells, a subset of T cells, DCs, and MDSCs—that represents a potential therapeutic target. Here, we discuss the role of CD244 in tumor-mediated immune cell regulation.

Chronic diabetic neuropathy is associated with peripheral demyelination and degeneration of nerve fibers. The mechanism(s) underlying neuronal injury in diabetic sensory neuropathy remain poorly understood. Recently, we reported increased expression and function of transient receptor potential vanilloid 1 (TRPV1) in large dorsal root ganglion (DRG) neurons in diabetic sensory neuropathy. In this study, we examined the effects of TRPV1 activation on cell injury pathways in this subpopulation of neurons in the streptozotocin‐induced diabetic rat model. Large DRG neurons from diabetic (6–8 weeks) rats displayed increased oxidative stress and activation of cell injury markers compared with healthy controls. Capsaicin (CAP) treatment induced decreased labeling of MitoTracker Red and increased cytosolic cytochrome c and activation of caspase 3 in large neurons isolated from diabetic rats. CAP treatment also induced oxidative stress in large diabetic DRG neurons, which was blocked by pre‐treatment with caspase or calpain inhibitor. In addition, both μ‐calpain expression and calpain activity were significantly increased in DRG neurons from diabetic rats after CAP treatment. Treatment with capsazepine, a competitive TRPV1 antagonist, markedly reduced these abnormalities in vitro and prevented activation of cell injury in large DRG neurons in diabetic rats in vivo. These results suggest that activation of the TRPV1 receptor activates pathways associated with caspase‐dependent and calpain‐dependent stress in large DRG neurons in STZ‐diabetic rats. Activation of the TRPV1 receptor may contribute to preferential neuronal stress in large DRG neurons relatively early in diabetic sensory neuropathy.

BackgroundDeveloping novel strategies to overcome the immunosuppressive tumor microenvironment is a critically important area of cancer therapy research. Here, we assess the therapeutic potential of CD244 (2B4/signaling lymphocyte activation molecule family 4), an immunoregulatory receptor found on a variety of immune cells, including exhausted CD8+T cells, dendritic cells (DCs), and myeloid-derived suppressor cells (MDSCs).MethodsUsing de-identified human tumor and blood samples from patients with head and neck squamous cell carcinoma (HNSCC) and HNSCC models in WT and CD244-/-mice, we assessed the therapeutic potential of CD244 using flow cytometry, RT-PCR, Luminex immunoassays and histopathological analyses.ResultsCompared with healthy tissues, tumor infiltrating CD8+T cells from HNSCC patients and a HNSCC mouse model showed significant increased expression of CD244 expression that correlated with PD1 expression. Moreover, CD244 was increased on intratumoral DC and MDSC and high CD244 expression correlated with PD-L1 expression and increased spontaneous expression of immune-suppressive mediators. In addition, CD244 activation inhibited production of proinflammatory cytokines in human DC in vitro. Importantly, CD244-/-mice showed significantly impaired tumor growth of HNSCC and interventional treatment of WT mice with anti-CD244 monoclonal antibody significantly impaired the growth of established HNSCC tumors and increased tumor-infiltrating CD8+T cells.ConclusionsTogether these data suggest that CD244 contributes to the overall immune-suppressive environment and therefore has potential as a new immunotherapy target in the treatment of malignancies.

Pazopanib provides a promising, well-tolerated therapy for DT/AF in the AYA population and warrants further study.

Malignant peripheral nerve sheath tumor (MPNST) is a rare soft‐tissue sarcoma with an unfavorable prognosis and limited therapeutic options. MPNSTs can be sporadic, but are often associated with neurofibromatosis (NF) 1 and usually arise from preexisting neurofibromas. MPNSTs in patients with NF2 have been reported in only exceedingly rare cases, and the mechanisms underlying transformation into an MPNST have not been fully elucidated. Here, we describe the clinicopathological and genomic features of a peripheral nerve sheath tumor (PNST), with a primary diagnosis of a neurofibroma, as it transforms into a high‐grade MPNST in the context of NF2.