Novel Opportunities for Cathepsin S Inhibitors in Cancer Immunotherapy by Nanocarrier-Mediated Delivery

Cathepsin S (CatS) is a secreted cysteine protease that cleaves certain extracellular matrix proteins, regulates antigen presentation in antigen-presenting cells (APC), and promotes M2-type macrophage and dendritic cell polarization. CatS is overexpressed in many solid cancers, and overall, it appears to promote an immune-suppressive and tumor-promoting microenvironment. While most data suggest that CatS inhibition or knockdown promotes anti-cancer immunity, cell-specific inhibition, especially in myeloid cells, appears to be important for therapeutic efficacy. This makes the design of CatS selective inhibitors and their targeting to tumor-associated M2-type macrophages (TAM) and DC an attractive therapeutic strategy compared to the use of non-selective immunosuppressive compounds or untargeted approaches. The selective inhibition of CatS can be achieved through optimized small molecule inhibitors that show good pharmacokinetic profiles and are orally bioavailable. The targeting of these inhibitors to TAM is now more feasible using nanocarriers that are functionalized for a directed delivery. This review discusses the role of CatS in the immunological tumor microenvironment and upcoming possibilities for a nanocarrier-mediated delivery of potent and selective CatS inhibitors to TAM and related APC to promote anti-tumor immunity.

Download Full-text

Computational and Experimental Progress on the Structure and Chemical Reactivity of Procyanidins: Their Potential as Metalloproteinases Inhibitors

Current Organic Chemistry ◽

10.2174/1385272822666180828114021 ◽

2019 ◽

Vol 23 (13) ◽

pp. 1403-1420

Author(s):

Ana María Mendoza-Wilson ◽

René Renato Balandrán-Quintana

Keyword(s):

Chemical Reactivity ◽

Direct Interaction ◽

Oral Intake ◽

Selective Inhibition ◽

Point Of View ◽

Matrix Proteins ◽

Regulatory Control ◽

Future Research ◽

Physiological Processes

Matrix metalloproteinases (MMPs) are enzymes involved in various physiological processes essential for living beings, but the loss of the regulatory control by endogenous inhibitors of MMPs, leads to the development of serious diseases such as cardiovascular system affections, cancer, and metastasis. For these reasons, exogenous inhibitors are required for these enzymes, which are able to control the proteolytic activity and are selective towards the different MMPs, besides properties which, from the pharmacological point of view, are necessary to be effective under physiological conditions. Based on these expectations, some bioactive compounds that are abundant in the human diet, like procyanidins (PCs) have emerged as potential exogenous inhibitors of MMPs. This review presents the advances of experimental and computational investigations carried out to date on the structure and chemical reactivity of PCs, to support the basis of their potential use as MMP inhibitors. For such purpose, specific sites among MMPs identified for a selective inhibition, the role of PCs in the regulation of MMPs by posttranscriptional mechanisms at the level of microRNAs, modulation of reactive oxygen species (ROS), effects on tissue inhibitors of MMPs (TIMPs), the crosslinking of PCs with the extracellular matrix proteins, as well as direct interaction between PCs and MMPs, are discussed. Methods for isolation and synthesis of PCs, as well as hydrophilicity properties, bioavailability, and susceptibility to be metabolized in oral intake, are also addressed. The information gathered in this review could additionally help to visualize future research related to this topic.

Download Full-text

The Role of TLRs in Anti-cancer Immunity and Tumor Rejection

Frontiers in Immunology ◽

10.3389/fimmu.2019.02388 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 23

Author(s):

Zuzanna Urban-Wojciuk ◽

Mohd M. Khan ◽

Benjamin L. Oyler ◽

Robin Fåhraeus ◽

Natalia Marek-Trzonkowska ◽

...

Keyword(s):

Tumor Rejection ◽

Cancer Immunity ◽

Anti Cancer

Download Full-text

Role of Methylation in Pro- and Anti-Cancer Immunity

Cancers ◽

10.3390/cancers13030545 ◽

2021 ◽

Vol 13 (3) ◽

pp. 545

Author(s):

Ali Mehdi ◽

Shafaat A. Rabbani

Keyword(s):

T Cells ◽

Transcriptional Regulation ◽

Immune Cells ◽

Cell Types ◽

Rna Methylation ◽

Dna And Rna ◽

Cancer Immunity ◽

Anti Cancer ◽

And Function

DNA and RNA methylation play a vital role in the transcriptional regulation of various cell types including the differentiation and function of immune cells involved in pro- and anti-cancer immunity. Interactions of tumor and immune cells in the tumor microenvironment (TME) are complex. TME shapes the fate of tumors by modulating the dynamic DNA (and RNA) methylation patterns of these immune cells to alter their differentiation into pro-cancer (e.g., regulatory T cells) or anti-cancer (e.g., CD8+ T cells) cell types. This review considers the role of DNA and RNA methylation in myeloid and lymphoid cells in the activation, differentiation, and function that control the innate and adaptive immune responses in cancer and non-cancer contexts. Understanding the complex transcriptional regulation modulating differentiation and function of immune cells can help identify and validate therapeutic targets aimed at targeting DNA and RNA methylation to reduce cancer-associated morbidity and mortality.

Download Full-text

Lipin-1, a Versatile Regulator of Lipid Homeostasis, Is a Potential Target for Fighting Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22094419 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4419

Author(s):

Laura Brohée ◽

Julie Crémer ◽

Alain Colige ◽

Christophe Deroanne

Keyword(s):

Lipid Metabolism ◽

Tumor Microenvironment ◽

Adjuvant Therapy ◽

Cancer Cells ◽

Therapeutic Strategy ◽

Lipid Homeostasis ◽

Cancer Therapies ◽

Anti Cancer ◽

Lipin 1

The rewiring of lipid metabolism is a major adaptation observed in cancer, and it is generally associated with the increased aggressiveness of cancer cells. Targeting lipid metabolism is therefore an appealing therapeutic strategy, but it requires a better understanding of the specific roles played by the main enzymes involved in lipid biosynthesis. Lipin-1 is a central regulator of lipid homeostasis, acting either as an enzyme or as a co-regulator of transcription. In spite of its important functions it is only recently that several groups have highlighted its role in cancer. Here, we will review the most recent research describing the role of lipin-1 in tumor progression when expressed by cancer cells or cells of the tumor microenvironment. The interest of its inhibition as an adjuvant therapy to amplify the effects of anti-cancer therapies will be also illustrated.

Download Full-text

IL-27R signaling serves as immunological checkpoint for NK cells to promote hepatocellular carcinoma

10.1101/2020.12.28.424635 ◽

2020 ◽

Author(s):

Turan Aghayev ◽

Iuliia O. Peshkova ◽

Aleksandra M. Mazitova ◽

Elizaveta K. Titerina ◽

Aliia R. Fatkhullina ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Nk Cells ◽

Nk Cell ◽

Inflammatory Diseases ◽

Cell Activity ◽

Cancer Immunity ◽

Anti Cancer ◽

Elevated Expression

AbstractHepatocellular carcinoma (HCC) is the most common form of liver cancer with poor survival and limited therapeutic options. HCC has different etiologies, typically associated with viral or carcinogenic insults or fatty liver disease and underlying chronic inflammation presents as a major unifying mechanism for tumor promotion. On the other hand, mechanisms of how inflammatory response can regulate anti-cancer immunity in HCC remain incompletely understood.Interleukin (IL)-27 receptor signaling plays an anti-inflammatory role in a variety of infectious and chronic inflammatory diseases. Here, using genetic and pharmacological approaches we found that IL-27 receptor (IL-27R) signaling promotes HCC development in vivo. Genetic loss of IL-27R suppressed HCC development in both toxin/carcinogen-induced diethylnitrosamine (DEN) and non-alcoholic steatohepatitis (NASH)-driven models. Elevated expression of IL-27RA rendered poor prognosis to HCC patients. Mechanistically, the pro-tumorigenic effect was mediated by immunoregulatory role of IL-27R signaling within the tumor microenvironment, particularly the suppression of Natural killer (NK) cells. IL-27R ablation enhanced the accumulation and activation of cytotoxic NK cells during acute liver injury and in HCC tumors, while depletion of NK cells abrogated the effect of genetic IL-27R disruption.Taken together, our data suggest an unexpected role of IL-27R signaling as a novel immunological checkpoint regulating NK cell activity and promoting development of HCC of different etiologies.

Download Full-text

Neddylation Regulates Macrophages and Implications for Cancer Therapy

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.681186 ◽

2021 ◽

Vol 9 ◽

Author(s):

Yanyu Jiang ◽

Lihui Li ◽

Yan Li ◽

Guangwei Liu ◽

Robert M. Hoffman ◽

...

Keyword(s):

Cancer Therapy ◽

Cancer Progression ◽

Therapeutic Strategy ◽

Cell Types ◽

Cellular Responses ◽

Present Review ◽

Biological Processes ◽

Cancer Immunity ◽

Anti Cancer ◽

Multiple Cell

Tumor-associated macrophages (TAMs) promote cancer progression via stimulating angiogenesis, invasion/metastasis, and suppressing anti-cancer immunity. Targeting TAMs is a potential promising cancer therapeutic strategy. Neddylation adds the ubiquitin-like protein NEDD8 to substrates, and thereby regulates diverse biological processes in multiple cell types, including macrophages. By controlling cellular responses, the neddylation pathway regulates the function, migration, survival, and polarization of macrophages. In the present review we summarized how the neddylation pathway modulates Macrophages and its implications for cancer therapy.

Download Full-text

The photoreceptor cytoskeleton visualized

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100122800 ◽

1992 ◽

Vol 50 (1) ◽

pp. 480-481

Author(s):

Beth Burnside

Keyword(s):

Outer Segment ◽

Pigment Epithelium ◽

Retinal Pigment ◽

Cell Polarization ◽

Synaptic Proteins ◽

Cell Functions ◽

Vertebrate Photoreceptor ◽

Numerous Cell ◽

Turn Over

The vertebrate photoreceptor provides a drammatic example of cell polarization. Specialized to carry out phototransduction at its distal end and to synapse with retinal interneurons at its proximal end, this long slender cell has a uniquely polarized morphology which is reflected in a similarly polarized cytoskeleton. Membranes bearing photopigment are localized in the outer segment, a modified sensory cilium. Sodium pumps which maintain the dark current critical to photosensory transduction are anchored along the inner segment plasma membrane between the outer segment and the nucleus.Proximal to the nucleus is a slender axon terminating in specialized invaginating synapses with other neurons of the retina. Though photoreceptor diameter is only 3-8u, its length from the tip of the outer segment to the synapse may be as great as 200μ. This peculiar linear cell morphology poses special logistical problems and has evoked interesting solutions for numerous cell functions. For example, the outer segment membranes turn over by means of a unique mechanism in which new disks are continuously added at the proximal base of the outer segment, while effete disks are discarded at the tip and phagocytosed by the retinal pigment epithelium. Outer segment proteins are synthesized in the Golgi near the nucleus and must be transported north through the inner segment to their sites of assembly into the outer segment, while synaptic proteins must be transported south through the axon to the synapse.The role of the cytoskeleton in photoreceptor motile processes is being intensely investigated in several laboratories.

Download Full-text