Radiation meets immunotherapy – a perfect match in the era of combination therapy?

Purpose This review focuses on recent advances in the field of combining radiation with immunotherapy for the treatment of malignant diseases, since various combinatorial cancer therapy approaches have lately proven highly successful. Results: With initial case reports and anecdotes progressively converting into solid clinical data, interest in cancer immunotherapy (CIT) has risen steeply. Especially immune checkpoint blockade therapies have recently celebrated tremendous successes in the treatment of severe malignancies resistant to conventional treatment strategies. Nevertheless, the high variability of patient responses to CIT remains a major hurdle, clearly indicating an urgent need for improvement. It has been suggested that successful cancer therapy most probably involves combinatorial treatment approaches. Radiotherapy (RT) has been proposed as a powerful partner for CIT due to its broad spectrum of immune modulatory characteristics. Several preclinical studies, supported by an increasing number of clinical observations, have demonstrated synergistic interactions between RT and CIT resulting in significantly improved therapy outcomes. Conclusions: Numerous reports have shown that radiation is capable of tipping the scales from tumor immune evasion to elimination in different tumor types. The next puzzle to be solved is the question of logistics – including types, schedule and dosage of combinatorial RT and CIT strategies

Compromised Blood-Brain Barrier Junctions Enhance Melanoma Cell Intercalation and Extravasation

Melanoma frequently metastasises to the brain, and a detailed understanding of the molecular and cellular mechanisms underlying melanoma cell extravasation across the blood-brain barrier (BBB) is important for preventing brain metastasis formation. Making use of primary mouse brain microvascular endothelial cells (pMBMECs) as an in vitro BBB model, we imaged the interaction of melanoma cells into pMBMEC monolayers. We observed exclusive junctional intercalation of melanoma cells and confirmed that melanoma-induced pMBMEC barrier disruption can be rescued by protease inhibition. Interleukin (IL)-1β stimulated pMBMECs or PECAM-1-knockout (-ko) pMBMECs were employed to model compromised BBB barrier properties in vitro and to determine increased melanoma cell intercalation compared to pMBMECs with intact junctions. The newly generated brain-homing melanoma cell line YUMM1.1-BrM4 was used to reveal increased in vivo extravasation of melanoma cells across the BBB of barrier-compromised PECAM-1-deficient mice compared to controls. Taken together, our data indicate that preserving BBB integrity is an important measure to limit the formation of melanoma-brain metastasis

Charting the immune landscape in brain cancers

The brain is one of the most complex organs of the human body. For a long time, it was thought that the brain is hermetically sheltered from entry by invaders, including our body's white blood cells. The discovery that different brain cancers contain quite distinct landscapes of immune cells may help us better understand their development and devise novel and effective therapeutic strategies

Loss of MAPK-activated protein kinase 2 enables potent dendritic cell-driven anti-tumour T cell response

Abstract Maintaining dendritic cells (DC) in a state of dysfunction represents a key mechanism by which tumour cells evade recognition and elimination by the immune system. Limited knowledge about the intracellular mediators of DC dysfunction restricts success of therapies aimed at reactivating a DC-driven anti-tumour immune response. Using a cell type-specific murine knock-out model, we have identified MAPK-activated protein kinase 2 (MK2) as a major guardian of a suppressive DC phenotype in the melanoma tumour microenvironment. MK2 deletion in CD11c+ cells led to an expansion of stimulatory CD103+ DCs, mounting a potent CD8+ T cell response that resulted in elimination of highly aggressive B16-F10 tumours upon toll-like receptor (TLR) activation in the presence of tumour antigen. Moreover, tumour infiltration by suppressive myeloid cells was strongly diminished. These insights into the regulation of DC functionality reveal MK2 as a targetable pathway for DC-centred immunomodulatory cancer therapies

Journal of Cellular and Molecular Medicine / Gliomasphere marker combinatorics: multidimensional flow cytometry detects CD 44+/CD 133+/ITGA 6+/CD 36+ signature

Glioblastoma is the most dangerous brain cancer. One reason for glioblastoma's aggressiveness are glioblastoma stemlike cells. To target them, a number of markers have been proposed (CD 133, CD 44, CD 15, A2B5, CD 36, CXCR 4, IL 6R, L1CAM , and ITGA 6). A comprehensive study of coexpression patterns of them has, however, not been performed so far. Here, we mapped the multidimensional coexpression profile of these stemnessassociated molecules. Gliomaspheres an established model of glioblastoma stemlike cells were used. Seven different gliomasphere systems were subjected to multicolor flow cytometry measuring the nine markers CD 133, CD 44, CD 15, A2B5, CD 36, CXCR 4, IL 6R, L1CAM , and ITGA 6 all simultaneously based on a novel 9marker multicolor panel developed for this study. The viSNE dimensionality reduction algorithm was applied for analysis. All gliomaspheres were found to express at least five different glioblastoma stemlike cell markers. Multidimensional analysis showed that all studied gliomaspheres consistently harbored a cell population positive for the molecular signature CD 44+/CD 133+/ITGA 6+/CD 36+. Glioblastoma patients with an enrichment of this combination had a significantly worse survival outcome when analyzing the two largest available The Cancer Genome Atlas datasets (MIT /Harvard Affymetrix: P = 0.0015, University of North Carolina Agilent: P = 0.0322). In sum, we detected a previously unknown marker combination demonstrating feasibility, usefulness, and importance of highdimensional gliomasphere marker combinatorics.(VLID)510252

A novel chemoradiation targeting stem and nonstem pancreatic cancer cells by repurposing disulfiram

Pancreatic ductal adenocarcinoma (PDAC) has a 5-year relative survival rate of 8% and is projected to be the second leading cause of cancer death by 2030, underscoring the urgency to develop new strategies to improve current therapeutic modalities for PDAC. Targeting pancreatic cancer stem cells (PCSCs), which are resistant to radiation and chemotherapy, is a promising strategy. A novel approach which can be readily clinically translated is to repurpose disulfiram (DSF), a drug for treating alcoholism, to target PCSCs. Chemoradiation or the combination of chemotherapy agents FOLFIRINOX, currently standard care for PDAC, can increase stemness in some established or primary PDAC cell lines. However, DSF in the presence of exogenously or endogenously supplied copper (Cu), when combined with chemotherapy or chemoradiation, targets both PCSCs and nonstem PDAC cells. Previously, we demonstrated that DSF/Cu effectively targets breast cancer stem cells in the context of fractionated radiation (FIR) by inhibiting the NF-κBâstemness gene pathway. Therefore, the hypothesis that PCSCs can be effectively targeted by incorporating DSF/Cu into the standard chemoradiation regimen consisting of 5-FU and FIR was investigated and found to be effective in vitro in targeting PCSCs, identified as either ALDHbrightor CD24+/CD44+/ESA+ or sphere-forming cells, as well as nonstem PDAC cells. In vivo, the combination of IR+5-FU+DSF/Cu was more effective (72.46%) than either IR+5-FU (30.32%) or IR+FOLFIRINOX therapy (43.04%) in inhibiting growth of the mouse Panc02 tumor. These encouraging results provide a solid foundation for clinical trials to improve the outcomes of the current standard chemoradiation therapy regimen for PDAC