Volume 5 (2021)

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

Beatrice Thier1,2 and Annette Paschen1,2

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 Ding2,3, 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

Previous

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

Beatrice Thier1,2 and Annette Paschen1,2

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 Ding2,3, 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

Previous

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

Previous

Elevated plasma levels of the appetite-stimulator ACBP/DBI in fasting and obese subjects

Sijing Li1-3,#, Adrien Joseph1-3,#, Isabelle Martins1,2 and Guido Kroemer1,2,4-6

INTRODUCTION Acyl coenzyme A binding protein (ACBP), which in humans is encoded by the gene DBI (diazepam binding inhibitor), is a phylogenetically ancient protein that is ubiquitously expressed by all

Spermidine supplementation in rare translation-associated disorders

Andreas Zimmermann1,2, Didac Carmona-Gutierrez1, and Frank Madeo1,2,3

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