Cuproptosis-related modification patterns depict the tumor microenvironment, precision immunotherapy, and prognosis of kidney renal clear cell carcinoma.

Background: Due to the different infiltration abundance of immune cells in tumor, the efficacy of immunotherapy varies widely among individuals. Recently, growing evidence suggested that cuproptosis has impact on cancer immunity profoundly. However, the comprehensive roles of cuproptosis-related genes in tumor microenvironment (TME) and in response to immunotherapy are still unclear. Methods: Based on 43 cuproptosis-related genes, we employed unsupervised clustering to identify cuproptosis-related patterns and single-sample gene set enrichment analysis algorithm to build a cuproptosis signature for individual patient's immune cell infiltration and efficacy of immune checkpoint blockade (ICB) evaluation. Then, the cuproptosis-related genes were narrowed down using univariate Cox regression model and least absolute shrinkage and selection operator algorithm. Finally, a cuproptosis risk score was built by random survival forest based on these narrowed-down genes. Results: Two distinct cuproptosis-related patterns were developed, with cuproptosis cluster 1 showing better prognosis and higher enrichment of immune-related pathways and infiltration of immune cells. For individual evaluation, the cuproptosis signature that we built could be used not only for predicting immune cell infiltration in TME but also for evaluating an individual's sensitivity to ICBs. Patients with higher cuproptosis signature scores exhibited more activated cancer immune processes, higher immune cell infiltration, and better curative efficacy of ICBs. Furthermore, a robust cuproptosis risk score indicated that patients with higher risk scores showed worse survival outcomes, which could be validated in internal and external validation cohorts. Ultimately, a nomogram which combined the risk score with the prognostic clinical factors was developed, and it showed excellent prediction accuracy for survival outcomes. Conclusion: Distinct cuproptosis-related patterns have significant differences on prognosis and immune cell infiltration in kidney renal clear cell carcinoma (KIRC). Cuproptosis signature and risk score are able to provide guidance for precision therapy and accurate prognosis prediction for patients with KIRC.

Metabolism of Dendritic Cells in Tumor Microenvironment: For Immunotherapy.

Dendritic cells (DCs) are a type of an antigen-presenting cell which undertake a job on capturing antigens coming from pathogens or tumors and presenting to T cells for immune response. The metabolism of DCs controls its development, polarization, and maturation processes and provides energy support for its functions. However, the immune activity of DCs in tumor microenvironment (TME) is inhibited generally. Abnormal metabolism of tumor cells causes metabolic changes in TME, such as hyperglycolysis, lactate and lipid accumulation, acidification, tryptophan deprivation, which limit the function of DCs and lead to the occurrence of tumor immune escape. Combined metabolic regulation with immunotherapy can strengthen the ability of antigen-presentation and T cell activation of DCs, improve the existing anti-tumor therapy, and overcome the defects of DC-related therapies in the current stage, which has great potential in oncology therapy. Therefore, we reviewed the glucose, lipid, and amino acid metabolism of DCs, as well as the metabolic changes after being affected by TME. Together with the potential metabolic targets of DCs, possible anti-tumor therapeutic pathways were summarized.

Rhes and AGS1/Dexras1 affect signaling by dopamine D1 receptors through adenylyl cyclase.

The GTP binding proteins Rhes and AGS1/Dexras1 define a subfamily of the Ras superfamily and have been shown to affect signaling by G-protein-coupled receptors. We tested the effects of both proteins at an early stage of signaling by dopamine receptors, activation of adenylyl cyclase. Rhes decreased dopamine D1 receptor agonist-stimulated cAMP accumulation in a pertussis toxin-sensitive manner. It had no effect on cAMP accumulation in the absence of agonist. AGS1/Dexras1, on the other hand, decreased cAMP accumulation in both vehicle-treated and agonist-treated cells, resulting in a higher percentage of stimulation by agonist or a higher signal-to-noise ratio. The effects of AGS1/Dexras1 on cAMP accumulation were not blocked by pertussis toxin, suggesting that it may produce these effects through interaction with a G(α) i monomer. Both Rhes and AGS1/Dexras1 were associated with GTP-bound G(α) i in pull-down assays. However, Rhes had no effect on the ability of activated D2 receptor to inhibit cAMP. Neither Rhes nor AGS1/Dexras1 interacted with the D1 receptor in pull-down assays. These findings show that, in addition to its well-known effects on signaling through Gi-coupled receptors, AGS1/Dexras1 can affect signaling through a Gs/olf-coupled receptor. Furthermore, the results suggest that Rhes exerts some of its effects by interacting with G(α) i.

Distinct pathways for the trafficking of angiotensin II and adrenergic receptors from the endoplasmic reticulum to the cell surface: Rab1-independent transport of a G protein-coupled receptor.

The molecular mechanism underlying the transport of G protein-coupled receptors from the endoplasmic reticulum (ER) to the cell surface is poorly understood. This issue was addressed by determining the role of Rab1, a Ras-related small GTPase that coordinates vesicular protein transport in the early secretory pathway, in the subcellular distribution and function of the angiotensin II type 1A receptor (AT1R), beta2-adrenergic receptor (AR), and alpha2B-AR in HEK293T cells. Inhibition of endogenous Rab1 function by transient expression of dominant-negative Rab1 mutants or Rab1 small interfering RNA (siRNA) induced a marked perinuclear accumulation and a significant reduction in cell-surface expression of AT1R and beta2-AR. The accumulated receptors were colocalized with calregulin (an ER marker) and GM130 (a Golgi marker), consistent with Rab1 function in regulating protein transport from the ER to the Golgi. In contrast, dominant-negative Rab1 mutants and siRNA had no effect on the subcellular distribution of alpha2B-AR. Similarly, expression of dominant-negative Rab1 mutants and siRNA depletion of Rab1 significantly attenuated AT1R-mediated inositol phosphate accumulation and ERK1/2 activation and beta2-AR-mediated ERK1/2 activation, but not alpha2B-AR-stimulated ERK1/2 activation. These data indicate that Rab1 GTPase selectively regulates intracellular trafficking and signaling of G protein-coupled receptors and suggest a novel, as yet undefined pathway for movement of G protein-coupled receptors from the ER to the cell surface.