Deficiencies in immune function that accumulate during cancer immunoediting lead to a progressive escape from host immune surveillance. Therapies that correct or overcome these defects could have a powerful impact on cancer management, but current knowledge of the types and mechanisms of immune escape are still incomplete. Here we report a novel mechanism of escape from T cell immunity that is caused by reduction in levels of the Delta family Notch ligands DLL1 and DLL4 in hematopoietic microenvironments. An important mediator of this effect was an elevation in the levels of circulating vascular endothelial growth factor (VEGF). Selective activation of the DLL1-Notch signaling pathway in bone marrow precursors enhanced T cell activation and inhibited tumor growth. Conversely, tumor growth led to inhibition of Delta family ligand signaling through Notch in the hematopoietic environment, resulting in suppressed T cell function. Overall, our findings uncover a novel mechanism of tumoral immune escape and suggest that a soluble multivalent form of DLL1 may offer a generalized therapeutic intervention to stimulate T cell immunity and suppress tumor growth.

Increased evidence of cross-talk between NK cells and other immune cells has enhanced the possibilities of exploiting the interplay between the activation and inhibition of NK cells for immunotherapeutic purposes. The battery of receptors possessed by NK cells help them to efficiently detect aberrant and infected cells and embark on the signaling pathways necessary to eliminate them. Endogenous expansion of NK cells and their effector mechanisms are under exploration for enhancing adoptive immunotherapy prospects in combination with immunostimulatory and cell-death-sensitizing treatments against cancer, viral infections and other pathophysiological autoimmune conditions. Various modes of NK cell manipulation are being undertaken to overcome issues such as relapse and graft rejections associated with adoptive immunotherapy. While tracing the remarkable properties of NK cells and the major developments in this field, we highlight the role of immune cooperativity in the betterment of current immunotherapeutic approaches.

Since the formulation of the tumour immunosurveillance theory, considerable focus has been on enhancing the effectiveness of host antitumour immunity, particularly with respect to T cells. A cancer evades or alters the host immune response by various ways to ensure its development and survival. These include modifications of the immune cell metabolism and T cell signaling. An inhibitory cytokine milieu in the tumour microenvironment also leads to immune suppression and tumour progression within a host. This review traces the development in the field and attempts to summarize the hurdles that the approach of adoptive T cell immunotherapy against cancer faces, and discusses the conditions that must be improved to allow effective eradication of cancer.

Sonic hedgehog (Shh) signaling is closely coupled with bioenergetics of medulloblastoma, the most common malignant pediatric brain tumor. Shh-associated medulloblastoma arises from cerebellar granule neuron precursors (CGNPs), a neural progenitor whose developmental expansion requires signaling by Shh, a ligand secreted by the neighboring Purkinje neurons. Previous observations show that Shh signaling inhibits fatty acid oxidation while driving increased fatty acid synthesis. Proliferating CGNPs and mouse Shh medulloblastomas feature high levels of glycolytic enzymes in vivo and in vitro. Since both of these metabolic processes are closely linked to mitochondrial bioenergetics, the role of Shh signaling in mitochondrial biogenesis was investigated. This report uncovers a surprising decrease in mitochondrial membrane potential (MMP) and overall ATP production in CGNPs exposed to Shh, consistent with increased glycolysis resulting in high intracellular acidity, leading to mitochondrial fragmentation. Ultrastructural examination of mitochondria revealed a spherical shape in Shh-treated cells, in contrast to the elongated appearance in vehicle-treated post-mitotic cells. Expression of Mitofusin 1 and 2 was reduced in these cells, while their ectopic expression restored the mitochondrial membrane potential to the non-proliferating state and the morphology to a fused, interconnected state. Mouse Shh medulloblastoma cells featured drastically impaired mitochondrial morphology, restoration of which by ectopic mitofusin expression was also associated with a decrease in the expression of Cyclin D2 protein, a marker for proliferation.