Despite great success in cancer immunotherapy, immune checkpoint-targeting drugs are not the most popular weapon in the armory of cancer therapy. Accumulating evidence suggests that the tumor immune ...microenvironment plays a critical role in anti-cancer immunity, which may result in immune checkpoint blockade therapy being ineffective, in addition to other novel immunotherapies in cancer patients. In the present review, we discuss the deficiencies of current cancer immunotherapies. More importantly, we highlight the critical role of tumor immune microenvironment regulators in tumor immune surveillance, immunological evasion, and the potential for their further translation into clinical practice. Based on their general targetability in clinical therapy, we believe that tumor immune microenvironment regulators are promising cancer immunotherapeutic targets. Targeting the tumor immune microenvironment, alone or in combination with immune checkpoint-targeting drugs, might benefit cancer patients in the future.
Despite the substantial impact of post-translational modifications on programmed cell death 1 ligand 1 (PD-L1), its importance in therapeutic resistance in pancreatic cancer remains poorly defined. ...Here, we demonstrate that never in mitosis gene A-related kinase 2 (NEK2) phosphorylates PD-L1 to maintain its stability, causing PD-L1-targeted pancreatic cancer immunotherapy to have poor efficacy. We identify NEK2 as a prognostic factor in immunologically "hot" pancreatic cancer, involved in the onset and development of pancreatic tumors in an immune-dependent manner. NEK2 deficiency results in the suppression of PD-L1 expression and enhancement of lymphocyte infiltration. A NEK binding motif (F/LXXS/T) is identified in the glycosylation-rich region of PD-L1. NEK2 interacts with PD-L1, phosphorylating the T194/T210 residues and preventing ubiquitin-proteasome pathway-mediated degradation of PD-L1 in ER lumen. NEK2 inhibition thereby sensitizes PD-L1 blockade, synergically enhancing the anti-pancreatic cancer immune response. Together, the present study proposes a promising strategy for improving the effectiveness of pancreatic cancer immunotherapy.
This paper considers the existence and uniqueness of positive solutions to a class of nonlinear systems of equations, which has wide applications in fluid mechanics and electrical circuit theory. In ...this paper, we define a new class of functions, called <inline-formula> <tex-math notation="LaTeX">{\mathcal{ M}} </tex-math></inline-formula>-type function, and then, we show some good properties of <inline-formula> <tex-math notation="LaTeX">{\mathcal{ M}} </tex-math></inline-formula>-type function as well as the relationship between this kind of functions and other kinds of functions. In particular, by fully exploiting the properties of <inline-formula> <tex-math notation="LaTeX">{\mathcal{ M}} </tex-math></inline-formula>-type function, we present that under a reasonable condition, the nonlinear system of equations with an <inline-formula> <tex-math notation="LaTeX">{\mathcal{ M}} </tex-math></inline-formula>-type function, which can be seen as a generalization of the multilinear system with a nonsingular <inline-formula> <tex-math notation="LaTeX">{\mathcal{ M}} </tex-math></inline-formula>-tensor, and a positive right-hand side vector has a unique positive solution. Meanwhile, for this class of problems, we give a preliminary and simple algorithm framework. What is more, under an additional assumption, we illustrate the feasibility of using Newton step when improving the original iteration algorithm to obtain better convergence. Numerical experiments show the stability and efficiency of the proposed algorithms.
Abstract
O
-linked β-
d
-
N
-acetylglucosamine (
O
-GlcNAc) is an important post-translational modification of serine or threonine residues on thousands of proteins in the nucleus and cytoplasm of ...all animals and plants. In eukaryotes, only two conserved enzymes are involved in this process.
O
-GlcNAc transferase is responsible for adding
O
-GlcNAc to proteins, while
O
-GlcNAcase is responsible for removing it. Aberrant
O
-GlcNAcylation is associated with a variety of human diseases, such as diabetes, cancer, neurodegenerative diseases, and cardiovascular diseases. Numerous studies have confirmed that
O
-GlcNAcylation is involved in the occurrence and progression of cancers in multiple systems throughout the body. It is also involved in regulating multiple cancer hallmarks, such as metabolic reprogramming, proliferation, invasion, metastasis, and angiogenesis. In this review, we first describe the process of
O
-GlcNAcylation and the structure and function of
O
-GlcNAc cycling enzymes. In addition, we detail the occurrence of
O
-GlcNAc in various cancers and the role it plays. Finally, we discuss the potential of
O
-GlcNAc as a promising biomarker and novel therapeutic target for cancer diagnosis, treatment, and prognosis.
VISTA (V-domain immunoglobulin suppressor of T cell activation) is a well-established immune regulatory receptor. However, pre-clinical investigations indicated more complicated influences of VISTA ...on cancer immunity than previously recognized. Here, we review the current knowledge on the therapeutic phenotypes and molecular mechanisms that underlie the contradictory roles of VISTA in checking anti-cancer immune responses. Furthermore, we highlight the potential indeterminacy of VISTA-targeted strategies in cancer immunotherapy, with in silico analyses. In fact, VISTA functions like a homeostatic regulator that actively normalizes immune responses. Thus, the regulatory role of VISTA in anti-cancer immunity remains to be fully elucidated.
Single-cell analysis is a valuable tool for dissecting cellular heterogeneity in complex systems
. However, a comprehensive single-cell atlas has not been achieved for humans. Here we use single-cell ...mRNA sequencing to determine the cell-type composition of all major human organs and construct a scheme for the human cell landscape (HCL). We have uncovered a single-cell hierarchy for many tissues that have not been well characterized. We established a 'single-cell HCL analysis' pipeline that helps to define human cell identity. Finally, we performed a single-cell comparative analysis of landscapes from human and mouse to identify conserved genetic networks. We found that stem and progenitor cells exhibit strong transcriptomic stochasticity, whereas differentiated cells are more distinct. Our results provide a useful resource for the study of human biology.
In this paper, we investigate the issue of maximizing the total equilibrium population with respect to resources distribution
m
(
x
) and diffusion rates
d
under the prescribed total amount of ...resources in a logistic model with nonlocal dispersals. Among other things, we show that for
d
≥
1
, there exist
C
0
,
C
1
>
0
, depending on
‖
m
‖
L
1
only, such that
C
0
d
≤
supremum of total population
≤
C
1
d
.
However, when replaced by random diffusion, a conjecture, proposed by Wei-Ming Ni and justified in Bai et al. (Proc. Am. Math. Soc. 144:2161–2170, 2016), indicates that in the one-dimensional case,
supremum of total population
=
3
‖
m
‖
L
1
.
This reflects serious discrepancies between models with local and nonlocal dispersal strategies. Furthermore, we provide an equivalent characterization about the combination of resource distribution and diffusion rate such that the corresponding total population could reach the optimal order
d
as
d
goes to infinity.
Tumor infiltrated type II (M2) macrophages promote tumorigenesis by suppressing immune clearance, promoting proliferation, and stimulating angiogenesis. Interestingly, macrophages were also found to ...enrich in small foci of altered hepatocytes containing liver tumor-initiating cells (TICs). However, whether and how TICs specifically recruit macrophages and the function of these macrophages in tumor initiation remain unknown due to technical difficulties. In this study, by generating genetically defined liver TICs, we demonstrate that TICs actively recruit M2 macrophages from as early as the single-cell stage. Elimination of TIC-associated macrophages (TICAMs) abolishes tumorigenesis in a manner dependent on the immune system. Mechanistically, activation of the Hippo pathway effector Yes-associated protein (YAP) underlies macrophage recruitment by TICs. These results demonstrate for the first time that macrophages play a decisive role in the survival of single TICs in vivo and provide a proof of principle for TIC elimination by targeting YAP or M2 macrophages.
Macrophages exist in most tissues of the body, where they perform various functions at the same time equilibrating with other cells to maintain immune responses in numerous diseases including cancer. ...Recently, emerging investigations revealed that metabolism profiles control macrophage phenotypes and functions, and in turn, polarization can trigger metabolic shifts in macrophages. Those findings implicate a special role of metabolism in tumor-associated macrophages (TAMs) because of the sophisticated microenvironment in cancer. Glucose is the major energy source of cells, especially for TAMs. However, the complicated association between TAMs and their glucose metabolism is still unclearly illustrated. Here, we review the recent advances in macrophage and glucose metabolism within the tumor microenvironment, and the significant transformations that occur in TAMs during the tumor progression. Additionally, we have also outlined the potential implications for macrophage-based therapies in cancer targeting TAMs.
Pancreatic cancer is a devastating disease that is characterized by persistent hypoxia. The roles of hypoxia-inducible factor-2α (hif-2α) are different to those of hif-1α, although both are critical ...for tumor cells to adapt to the hypoxic microenvironment. However, unlike the well-studied hif-1α, the role of hif-2α in tumors, including pancreatic cancer, is poorly understood.
Herein, we used a mutated hif-2α (A530T) to figure out the problem that wild-type hif-2α is quickly degraded which limits the study of its function. Using several cell lines, mouse models, and human tissues, we obtained a general picture of hif-2α in pancreatic cancer progression.
Functional assays revealed that hif-2α promotes epithelial-to-mesenchymal transition, enhances tumor proliferation and invasion, increases stemness, facilitates angiogenesis, and up-regulates aerobic glycolysis. We identified an interaction between hif-2α and β-catenin, and found that hif-2α/β-catenin complex formation increased the activity of β-catenin and the protein stability of hif-2α. In vivo study confirmed the pro-oncogenic role of hif-2α, whose expression correlated with those of E-cadherin, vimentin, Ki-67, and CD31, but not hif-1α. A human tissue study showed that hif-2α was associated with lymph node metastasis, pathological grade, stroma abundance, vascularization and patient survival. High expression of hif-2α was also identified as an independent indicator of poor prognosis in patients with pancreatic cancer.
Our systematic study revealed the roles of hif-2α in pancreatic cancer, and may provide a novel target for this highly malignant disease.
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