Volume 5 (2021)

Innate RIG-I signaling restores antigen presentation in tumors and overcomes T cell resistance

Beatrice Thier^1,2 and Annette Paschen^1,2

In recent years, therapy with immune modulating antibodies, termed immune checkpoint blockade (ICB), has revolutionized the treatment of advanced metastatic melanoma, yielding long-lasting clinical responses in a subgroup of patients. But despite this remarkable progress, resistance to therapy represents a major clinical challenge. ICB efficacy is critically dependent on cytotoxic CD8+ T cells targeting tumor cells in an HLA class I (HLA-I) antigen-dependent manner. Transcriptional suppression of the HLA-I antigen processing and presentation machinery (HLA-I APM) in melanoma cells leads to HLA-I-low/-negative tumor cell phenotypes escaping CD8+ T cell recognition and contributing to ICB resistance. In general, HLA-I-low/-negative tumor cells can be re-sensitized to T cells by interferons (IFN), augmenting HLA-I APM expression. However, this mechanism fails when melanoma cells acquire resistance to IFN, which recently turned out as a key resistance mechanism in (...)

Improving glucose and lipids metabolism: drug development based on bile acid related targets

Hanchen Shen¹, Lili Ding^2,3, Mehdi Baig³, Jingyan Tian⁴, Yang Wang¹ and Wendong Huang³

Bariatric surgery is one of the most effective treatment options for severe obesity and its comorbidities. However, it is a major surgery that poses several side effects and risks which impede its clinical use. Therefore, it is urgent to develop alternative safer pharmacological approaches to mimic bariatric surgery. Recent studies suggest that bile acids are key players in mediating the metabolic benefits of bariatric surgery. Bile acids can function as signaling molecules by targeting bile acid nuclear receptors and membrane receptors, like FXR and TGR5 respectively. In addition, the composition of bile acids is regulated by either the hepatic sterol enzymes such as CYP8B1 or the gut microbiome. These bile acid related targets all play important roles in regulating metabolism. Drug development based on these targets could provide new hope for patients without the risks of surgery and at a lower cost. In this review, we summarize the most updated progress on bile acid related targets and development of small molecules as drug candidates based on these targets.

Mitochondrial dynamics links PINCH-1 signaling to proline metabolic reprogramming and tumor growth

Ling Guo¹ and Chuanyue Wu²

How does PINCH-1 regulate proline synthesis? Proline is synthesized in cells through reduction of Δ1-pyrroline-5-carboxylate (P5C) with NAD(P)H as an electron donor, a reaction catalyzed by pyrroline-5-carboxylate reductase (PYCR). Three

To promote or inhibit glioma progression, that is the question for IL-33

Stephen M. Robbins¹ and Donna L. Senger¹

Glioblastoma represents one of the most fatal of human cancers. Although there has been progress in the treatment of glioblastoma as a result of a treatment regimen that combines maximal

Cellular mechanisms linking cancers to obesity

Xiao-Zheng Liu^1,#, Line Pedersen^1,# and Nils Halberg¹

Obesity is epidemiologically linked to 13 forms of cancer. The local and systemic obese environment is complex and likely affect tumors through multiple avenues. This includes modulation of cancer cell phenotypes and the composition of the tumor microenvironment. A molecular understanding of how obesity links to cancer holds promise for identifying candidate genes for targeted therapy for obese cancer patient. Herein, we review both the cell-autonomous and non-cell-autonomous mechanisms linking obesity and cancer as well as provide an overview of the mouse model systems applied to study this.

Inhibitory DAMPs in immunogenic cell death and its clinical implications

Kazukuni Hayashi^1,2, Fotis Nikolos³ and Keith S. Chan^1,3

– [table id=388/] INHIBITORY DAMP OR INHIBITORY DAMPS? How are immunostimulatory DAMPs shut off? Under normal physiological conditions, the co-stimulatory molecules, CD80/86, on antigen presenting cells bind to the co-activating

Roles of phosphatidyl inositol 3 kinase gamma (PI3Kγ) in respiratory diseases

Valentina Sala¹, Angela Della Sala¹, Alessandra Ghigo^1,2,# and Emilio Hirsch^1,2,#

Phosphatidyl inositol 3 kinase gamma (PI3Kγ) is expressed in all the cell types that are involved in airway inflammation and disease, including not only leukocytes, but also structural cells, where it is expressed at very low levels under physiological conditions, while is significantly upregulated after stress. In the airways, PI3Kγ behaves as a trigger or a controller, depending on the pathological context. In this review, the contribution of PI3Kγ in a plethora of respiratory diseases, spanning from acute lung injury, pulmonary fibrosis, asthma, cystic fibrosis and response to both bacterial and viral pathogens, will be commented.

Spermidine supplementation in rare translation-associated disorders

Andreas Zimmermann^1,2, Didac Carmona-Gutierrez¹, and Frank Madeo^1,2,3

Spermidine is a naturally occurring polyamine that is strongly involved in manifold cellular processes, for example, DNA, RNA and protein stabilization, cell growth, proliferation, autophagy, and aging. Importantly, spermidine has

Targeting FBXO44/SUV39H1 elicits tumor cell-specific DNA replication stress and viral mimicry

Jia Z. Shen¹ and Charles Spruck¹

Repetitive elements (REs) are normally transcriptionally silenced in somatic cells by repressive epigenetic modifications, which are thought to include DNA methylation and histone modifications such as deacetylation, H3K9me3, and H4K20me3. Although, it is unclear how RE silencing is maintained through DNA replication cycles in rapidly growing cancer cells. On the other hand, the reactivation of endogenous retroelements beyond a threshold level of tolerance in cancer cells, such as by treatment with DNA demethylating agents or HDAC or LSD1 inhibitors, can induce viral mimicry responses that augment certain cancer therapies, including immunotherapy. However, these agents can also affect normal cells presenting obvious side effects. Therefore, uncovering cancer cell-specific RE silencing mechanisms could provide a basis for the development of a new generation of cancer (...)

The OFD1 protein is a novel player in selective autophagy: another tile to the cilia/autophagy puzzle

Manuela Morleo¹ and Brunella Franco^1,2

Autophagy is an evolutionary conserved and highly regulated cellular degradation pathway which entails the engulfment of cellular components into double-membrane vesicles, called autophagosomes, which then fuse with lysosomes to degrade

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