studies-chaperone-cochaperone-interactions-using-homogenous-bead

Studies of Chaperone-Cochaperone Interactions using Homogenous Bead-Based Assay

Targeting the heat shock protein 90 (Hsp90)-cochaperone interactions provides the possibility to specifically regulate Hsp90-dependent intracellular ...

Karolinska Institutet

During tumorigenesis, tumor infiltrating regulatory T (Treg) cells restrict the function of effector T cells in tumor microenvironment and thereby promoting tumor growth. The anti-tumor activity of effector T cells can be therapeutically unleashed, and is now being exploited for the treatment of various types of human cancers. However, the immune suppressive function of Treg cells remains a major hurdle to broader effectiveness of tumor immunotherapy. In this article, we reported that the deletion of Bcl6 specifically in Treg cells led to stunted tumor growth, which was caused by impaired Treg cell responses. Notably, Bcl6 is essential in maintaining the lineage stability of Treg cells in tumor microenvironment. Meanwhile, we found that the absence of follicular regulatory T (Tfr) cells, which is a result of Bcl6 deletion in Foxp3 cells, was dispensable for tumor control. Importantly, the increased Bcl6 expression in Treg cells is associated with poor prognosis of human colorectal cancer and lymph node metastasis of skin melanoma. Furthermore, Bcl6 deletion in Treg cells exhibits synergistic effects with immune checkpoint blockade therapy. Collectively, these results indicate that Bcl6 actively participates in regulating Treg cell immune responses during tumorigenesis and can be exploited as a therapeutic target of anti-tumor immunity.

Bcl6 Preserves the Suppressive Function of Regulatory T Cells During Tumorigenesis.

Alzheimer's disease (AD) is the most common form of dementia characterized by presence of extracellular amyloid plaques and intracellular neurofibrillary tangles composed of tau protein. Currently there are close to 50 million people living with dementia and this figure is expected to increase to 75 million by 2030 putting a huge burden on the economy due to the health care cost. Considering the effects on quality of life of patients and the increasing burden on the economy, there is an enormous need of new disease modifying therapies to tackle this disease. The current therapies are dominated by only symptomatic treatments including cholinesterase inhibitors and N-methyl-D-aspartate receptor blockers but no disease modifying treatments exist so far. After several failed attempts to develop drugs against amyloidopathy, tau targeting approaches have been in the main focus of drug development against AD. After an overview of the tauopathy in AD, this review summarizes recent findings on the development of small molecules as therapeutics targeting tau modification, aggregation, and degradation, and tau-oriented multi-target directed ligands. Overall, this work aims to provide a comprehensive and critical overview of small molecules which are being explored as a lead candidate for discovering drugs against tauopathy in AD.

Small molecule therapeutics for tauopathy in Alzheimer's disease: Walking on the path of most resistance.

Glioblastoma is the most malignant cancer in the brain and currently incurable. It is urgent to identify effective targets for this lethal disease. Inhibition of such targets should suppress the growth of cancer cells and, ideally also precancerous cells for early prevention, but minimally affect their normal counterparts. Using genetic mouse models with neural stem cells (NSCs) or oligodendrocyte precursor cells (OPCs) as the cells-of-origin/mutation, it is shown that the susceptibility of cells within the development hierarchy of glioma to the knockout of insulin-like growth factor I receptor (IGF1R) is determined not only by their oncogenic states, but also by their cell identities/states. Knockout of IGF1R selectively disrupts the growth of mutant and transformed, but not normal OPCs, or NSCs. The desirable outcome of IGF1R knockout on cell growth requires the mutant cells to commit to the OPC identity regardless of its development hierarchical status. At the molecular level, oncogenic mutations reprogram the cellular network of OPCs and force them to depend more on IGF1R for their growth. A new-generation brain-penetrable, orally available IGF1R inhibitor harnessing tumor OPCs in the brain is also developed. The findings reveal the cellular window of IGF1R targeting and establish IGF1R as an effective target for the prevention and treatment of glioblastoma.

Oncogenic State and Cell Identity Combinatorially Dictate the Susceptibility of Cells within Glioma Development Hierarchy to IGF1R Targeting.

Mammalian spermatogenesis is a biological process of male gamete formation. Gonocytes are the only precursors of spermatogonial stem cells (SSCs) which develop into mature spermatozoa. DDX5 is one of DEAD-box RNA helicases and expresses in male germ cells, suggesting that Ddx5 plays important functions during spermatogenesis. Here, we explore the functions of Ddx5 in regulating the specification of gonocytes.

RNA helicase DDX5 acts as a critical regulator for survival of neonatal mouse gonocytes.

The adaptive immunity that protects patients from coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is not well characterized. In particular, the asymptomatic patients have been found to induce weak and transient SARS-CoV-2 antibody responses, but the underlying mechanisms remain unknown; meanwhile, the protective immunity that guide the recovery of these asymptomatic patients is elusive. Here, we characterized SARS-CoV-2-specific B-cell and T-cell responses in 10 asymptomatic patients and 64 patients with other disease severity (mild, n = 10, moderate, n = 32, severe, n = 12) and found that asymptomatic or mild symptomatic patients failed to mount virus-specific germinal center (GC) B cell responses that result in robust and prolonged humoral immunity, assessed by GC response indicators including follicular helper T (T) cell and memory B cell responses as well as serum CXCL13 levels. Alternatively, these patients mounted potent virus-specific T1 and CD8 T cell responses. In sharp contrast, patients of moderate or severe disease induced vigorous virus-specific GC B cell responses and associated T responses; however, the virus-specific T1 and CD8 T cells were minimally induced in these patients. These results, therefore, uncovered the protective immunity in asymptomatic patients and also revealed the strikingly dichotomous and incomplete humoral and cellular immune responses in COVID-19 patients with different disease severity, providing important insights into rational design of effective COVID-19 vaccines.

The dichotomous and incomplete adaptive immunity in COVID-19 patients with different disease severity.

Follicular regulatory T cells (Tfrs), a specialized subset of regulatory T cells (Tregs), have a particular role in the control of follicular helper T cell-driven germinal center (GC) responses. Following differentiation signals similar to those received by follicular helper T cells (Tfhs), Tfrs gain expression of characteristic chemokine receptors and transcription factors, such as CXCR5 and Bcl-6, allowing them to migrate into the B-cell follicle and perform in situ suppression. Thus, together with Tfhs, Tfrs help maintaining an optimized GC-reaction. However, the mechanism underlying the Treg-to-Tfr transition remains obscure. Here, we established a highly reproducible protocol for investigating the differentiation of Tregs into Tfrs by constructing spleen-chimeric mice combined with retrovirus transduction. We demonstrated that using this strategy, over 4 folds of Tregs could differentiate into Tfrs in Bcl-6 overexpression group compared to control counterparts (Migr1), and Bcl-6 could efficiently promote Tfr differentiation during acute viral infection. Hence, this method provides us an easy access to investigate the factors that regulate the differentiation program that converts Tregs into Tfrs, which will enhance our understanding of the networks regulating GC-reaction and shed new light on the molecular basis of immune homeostasis.

A novel strategy to investigate the factors regulating the Treg to Tfr transition during acute viral infection.

Antitumor therapeutic vaccines are generally based on antigenic epitopes presented by major histocompatibility complex (MHC-I) molecules to induce tumor-specific CD8 T cells. Paradoxically, continuous T cell receptor (TCR) stimulation from tumor-derived CD8 T-cell epitopes can drive the functional exhaustion of tumor-specific CD8 T cells. Tumor-specific type-I helper CD4 T (T1) cells play an important role in the population maintenance and cytotoxic function of exhausted tumor-specific CD8 T cells in the tumor microenvironment. Nonetheless, whether the vaccination strategy targeting MHC-II-restricted CD4 T-cell epitopes to induce tumor-specific T1 responses can confer effective antitumor immunity to restrain tumor growth is not well studied. Here, we developed a heterologous prime-boost vaccination strategy to effectively induce tumor-specific T1 cells and evaluated its antitumor efficacy and its capacity to potentiate PD-1/PD-L1 immunotherapy.

CD4 T-cell epitope-based heterologous prime-boost vaccination potentiates anti-tumor immunity and PD-1/PD-L1 immunotherapy.

Cytotoxic CD8 T cells are the main focus of efforts to understand anti-tumor immunity and immunotherapy. The adoptive transfer of tumor-reactive cytotoxic CD8 T lymphocytes expanded and differentiated  has long been considered the primary strategy in adaptive anti-tumor immunity, however, the majority of the transferred tumor antigen-specific CD8 T cells differentiated into CD39CD69 exhausted progenies, limiting its effects in repressing tumor growth. Contrarily, less attention has been addressed to the role of CD4 T cells during tumorigenesis. Using a mouse model of metastatic melanoma, we found that transferring tumor-specific CD4 T cells into recipients induces substantial regression of the established metastatic tumors. Notably,  activated CD4 T cells developed into cytotoxic CD4 T cells  and get exhausted gradually. The blockade of PD-L1 signaling resulted in an expansion of tumor specific CD4 T cells, which could better control the established metastatic melanoma. Moreover, the tumor-specific memory CD4 T cell can prevent mice from tumor metastasis, and the tumor-specific effector CD4 T cells can also mitigate the established metastatic tumor. Overall, our findings suggest a novel mechanism of CD4 T cells in curtailing tumor metastasis and confirm their therapeutic role in combination with PD-L1 blockade in cancer immunotherapy. Hence, a better understanding of cytotoxic CD4 T cell-mediated tumor regression could provide an alternative choice for patients exhibiting suboptimal or no response to CD8 T cell-based immunotherapies.

Tumor-Specific CD4 T Cells Restrain Established Metastatic Melanoma by Developing Into Cytotoxic CD4 T Cells.

Blocking PD-1/PD-L1 signaling transforms cancer therapy and is assumed to unleash exhausted tumor-reactive CD8 T cells in the tumor microenvironment (TME). However, recent studies have also indicated that the systemic tumor-reactive CD8 T cells may respond to PD-1/PD-L1 immunotherapy. These discrepancies highlight the importance of further defining tumor-specific CD8 T cell responders to PD-1/PD-L1 blockade. Here, using multiple preclinical tumor models, we revealed that a subset of tumor-specific CD8 cells in the tumor draining lymph nodes (TdLNs) was not functionally exhausted but exhibited canonical memory characteristics. TdLN-derived tumor-specific memory (T) cells established memory-associated epigenetic program early during tumorigenesis. More importantly, TdLN-T cells exhibited superior anti-tumor therapeutic efficacy after adoptive transfer and were characterized as bona fide responders to PD-1/PD-L1 blockade. These findings highlight that TdLN-T cells could be harnessed to potentiate anti-tumor immunotherapy.

The primordial differentiation of tumor-specific memory CD8 T cells as bona fide responders to PD-1/PD-L1 blockade in draining lymph nodes.

Tumor-specific memory CD8 T cells are strictly resident in draining lymph nodes during tumorigenesis.

Author Correction: Tumor-specific memory CD8 T cells are strictly resident in draining lymph nodes during tumorigenesis.

Although DNA mutation drives stem cell aging, how mutation-accumulated stem cells obtain clonal advantage during aging remains poorly understood. Here, using a mouse model of irradiation-induced premature aging and middle-aged mice, we show that DNA mutation accumulation in hematopoietic stem cells (HSCs) during aging upregulates their surface expression of major histocompatibility complex class II (MHCII). MHCII upregulation increases the chance for recognition by bone marrow (BM)-resident regulatory T cells (Tregs), resulting in their clonal expansion and accumulation in the HSC niche. On the basis of the establishment of connexin 43 (Cx43)-mediated gap junctions, BM Tregs transfer cyclic adenosine monophosphate (cAMP) to aged HSCs to diminish apoptotic priming and promote their survival via activation of protein kinase A (PKA) signaling. Importantly, targeting the HSC-Treg interaction or depleting Tregs effectively prevents the premature/physiological aging of HSCs. These findings show that aged HSCs use an active self-protective mechanism by entrapping local Tregs to construct a prosurvival niche and obtain a clonal advantage.

Aged hematopoietic stem cells entrap regulatory T cells to create a prosurvival microenvironment.

This study explored the structure and biological activities of a novel polysaccharide, PRY1-1, isolated from red yeast rice (RYR) through solid-state fermentation and biotransformation by Monascus purpureus. The structure of PRY1-1 was characterized by Fourier-transform infrared (FTIR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, and other analytical techniques, revealing distinct differences from previously identified mycelial and extracellular polysaccharides. Functional assessments were performed on high-fat diet (HFD)-induced mice to evaluate the impact of PRY1-1 on lipid metabolism and gut function. The results demonstrated that PRY1-1 effectively ameliorated HFD-induced lipid metabolism disorders in the liver and epididymal white adipose tissue (eWAT) by regulating the levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), leptin, adiponectin. Additionally, PRY1-1 protected gut function by enhancing gut barrier integrity, modulating gut microbiota composition, and regulating gut metabolite levels. This study offers new insights into the mechanisms by which RYR polysaccharides influence lipid metabolism, highlighting the potential of PRY1-1 as a functional component with significant health benefits.

Structural characterization of red yeast rice-derived polysaccharide and its promotion of lipid metabolism and gut function in high-fat diet-induced mice.

Article	Year
Bcl6 Preserves the Suppressive Function of Regulatory T Cells During Tumorigenesis. Frontiers in immunology\| PubMed ID: 32477338	2020
Small molecule therapeutics for tauopathy in Alzheimer's disease: Walking on the path of most resistance. European journal of medicinal chemistry\| PubMed ID: 33139110	2021
Oncogenic State and Cell Identity Combinatorially Dictate the Susceptibility of Cells within Glioma Development Hierarchy to IGF1R Targeting. Advanced science (Weinheim, Baden-Wurttemberg, Germany)\| PubMed ID: 33173731	2020
RNA helicase DDX5 acts as a critical regulator for survival of neonatal mouse gonocytes. Cell proliferation\| PubMed ID: 33666296	2021
The dichotomous and incomplete adaptive immunity in COVID-19 patients with different disease severity. Signal transduction and targeted therapy\| PubMed ID: 33686064	2021
A novel strategy to investigate the factors regulating the Treg to Tfr transition during acute viral infection. Journal of immunological methods\| PubMed ID: 35398062	2022
CD4 T-cell epitope-based heterologous prime-boost vaccination potentiates anti-tumor immunity and PD-1/PD-L1 immunotherapy. Journal for immunotherapy of cancer\| PubMed ID: 35580929	2022
Tumor-Specific CD4 T Cells Restrain Established Metastatic Melanoma by Developing Into Cytotoxic CD4 T Cells. Frontiers in immunology\| PubMed ID: 35784297	2022
The primordial differentiation of tumor-specific memory CD8 T cells as bona fide responders to PD-1/PD-L1 blockade in draining lymph nodes. Cell\| PubMed ID: 36208623	2022
Tumor-specific memory CD8 T cells are strictly resident in draining lymph nodes during tumorigenesis. Cellular & molecular immunology\| PubMed ID: 36859455	2023
Author Correction: Tumor-specific memory CD8 T cells are strictly resident in draining lymph nodes during tumorigenesis. Cellular & molecular immunology\| PubMed ID: 37225839	2023
Aged hematopoietic stem cells entrap regulatory T cells to create a prosurvival microenvironment. Cellular & molecular immunology\| PubMed ID: 37644165	2023
Structural characterization of red yeast rice-derived polysaccharide and its promotion of lipid metabolism and gut function in high-fat diet-induced mice. International journal of biological macromolecules\| PubMed ID: 39433195	2024

Lisha Wang

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