The cell-surface glycoprotein CD44 is involved in a multitude of important physiological functions including cell proliferation, adhesion, migration, hematopoiesis, and lymphocyte activation. The diverse physiological activity of CD44 is manifested in the pathology of a number of diseases including cancer, arthritis, bacterial and viral infections, interstitial lung disease, vascular disease and wound healing. This diversity in biological activity is conferred by both a variety of distinct CD44 isoforms generated through complex alternative splicing, posttranslational modifications (e.g., N- and O-glycosylation), interactions with a number of different ligands and the abundance and spatial distribution of CD44 on the cell surface. The extracellular matrix glycosaminoglycan hyaluronan (HA) is the principle ligand of CD44. This review focuses both CD44-hyaluronan dependent and independent CD44 signaling and the role of CD44-HA interaction in various pathophysiologies. The review also discusses recent advances in novel treatment strategies that exploit the CD44-HA interaction either for direct targeting or for drug delivery.

/pdf/the-role-of-cd44-in-disease-pathophysiology-and-targeted-40tcq7ikrn.pdf

The Role of CD44 in Disease Pathophysiology and Targeted Treatment

Inhibition of antitumor T cell responses can be mediated by the productive interaction between the programmed death-1 (PD-1) receptor on T cells and its ligand PD-L1 PD-L1 is highly expressed on both murine bone marrow-derived dendritic cells (DCs) and B16 melanoma In this study, in vitro blockade of PD-L1 interaction on DCs led to enhanced IFN-gamma production and cytotoxicity by Ag-specific T cells In vivo, the systemic administration of anti-PD-L1 Ab plus melanoma peptide-pulsed DCs resulted in a higher number of melanoma peptide-specific CD8(+) T cells, but this combination was insufficient to delay the growth of established B16 melanoma Although the addition of 600 rad of total body irradiation delayed tumor growth, further adoptive transfer of Ag-specific CD8(+) T cells was needed to achieve tumor regression and long-term survival of the treated mice Lymphopenic mice treated with anti-PD-L1 Ab demonstrated increased activation and persistence of adoptively transferred T cells, including a higher number of CD8(+) T cells infiltrating the tumor mass Together, these studies support the blocking of PD-L1 signaling as a means to enhance combined immunotherapy approaches against melanoma

Blockade of Programmed Death Ligand 1 Enhances the Therapeutic Efficacy of Combination Immunotherapy against Melanoma

Hyaluronic acid or hyaluronan (HA) is perhaps one of the most uncomplicated large polymers that regulates several normal physiological processes and, at the same time, contributes to the manifestation of a variety of chronic and acute diseases, including cancer. Members of the HA signaling pathway (HA synthases, HA receptors, and HYAL-1 hyaluronidase) have been experimentally shown to promote tumor growth, metastasis, and angiogenesis, and hence each of them is a potential target for cancer therapy. Furthermore, as these members are also overexpressed in a variety of carcinomas, targeting of the HA family is clinically relevant. A variety of targeted approaches have been developed to target various HA family members, including small-molecule inhibitors and antibody and vaccine therapies. These treatment approaches inhibit HA-mediated intracellular signaling that promotes tumor cell proliferation, motility, and invasion, as well as induction of endothelial cell functions. Being nontoxic, nonimmunogenic, and versatile for modifications, HA has been used in nanoparticle preparations for the targeted delivery of chemotherapy drugs and other anticancer compounds to tumor cells through interaction with cell-surface HA receptors. This review discusses basic and clinical translational aspects of targeting each HA family member and respective treatment approaches that have been described in the literature.

/pdf/targeting-hyaluronic-acid-family-for-cancer-chemoprevention-32h6ytveyi.pdf

Targeting Hyaluronic Acid Family for Cancer Chemoprevention and Therapy

Many clinical trials have been carried out or are in progress to assess the therapeutic potential of dendritic-cell- (DC-) based vaccines on cancer patients, and recently the first DC-based vaccine for human cancer was approved by the FDA. Herewith, we describe the general characteristics of DCs and different strategies to generate effective antitumor DC vaccines. In recent years, the relevance of the tumor microenvironment in the progression of cancer has been highlighted. It has been shown that the tumor microenvironment is capable of inactivating various components of the immune system responsible for tumor clearance. In particular, the effect of the tumor microenvironment on antigen-presenting cells, such as DCs, does not only render these immune cells unable to induce specific immune responses, but also turns them into promoters of tumor growth. We also describe strategies likely to increase the efficacy of DC vaccines by reprogramming the immunosuppressive nature of the tumor microenvironment.

/pdf/dendritic-cells-the-tumor-microenvironment-and-the-la5qupc90l.pdf

Dendritic cells the tumor microenvironment and the challenges for an effective antitumor vaccination.

Cancer is a malignant tumor that threatens the health of human beings, and has become the leading cause of death in urban and rural residents in China. The glycocalyx is a layer of multifunctional glycans that covers the surfaces of a variety of cells, including vascular endothelial cells, smooth muscle cells, stem cells, epithelial, osteocytes, as well as cancer cells. The glycosylation and syndecan of cancer cell glycocalyx are unique. However, heparan sulfate (HS), hyaluronic acid (HA), and syndecan are all closely associated with the processes of cancer progression, including cell migration and metastasis, tumor cell adhesion, tumorigenesis, and tumor growth. The possible underlying mechanisms may be the interruption of its barrier function, its radical role in growth factor storage, signaling, and mechanotransduction. In the later sections, we discuss glycocalyx targeting therapeutic approaches reported in animal and clinical experiments. The study concludes that cancer cells’ glycocalyx and its role in cancer progression are beginning to be known by more groups, and future studies should pay more attention to its mechanotransduction of interstitial flow-induced shear stress, seeking promising therapeutic targets with less toxicity but more specificity.

https://www.mdpi.com/1422-0067/19/9/2484/pdf

Cancer Cell Glycocalyx and Its Significance in Cancer Progression

Immune infiltration is typically quantified using cellular density, not accounting for cellular clustering. Tumor-associated macrophages (TAM) activate oncogenic signaling through paracrine interactions with tumor cells, which may be better reflected by local cellular clustering than global density metrics. Using multiplex immunohistochemistry and digital pathologic analysis we quantified cellular density and cellular clustering for myeloid cell markers in 129 regions of interest from 55 samples from 35 patients with metastatic ccRCC. CD68+ cells were found to be clustered with tumor cells and dispersed from stromal cells, while CD163+ and CD206+ cells were found to be clustered with stromal cells and dispersed from tumor cells. CD68+ density was not associated with OS, while high tumor/CD68+ cell clustering was associated with significantly worse OS. These novel findings would not have been identified if immune infiltrate was assessed using cellular density alone, highlighting the importance of including spatial analysis in studies of immune cell infiltration of tumors. Significance: Increased clustering of CD68+ TAMs and tumor cells was associated with worse overall survival for patients with metastatic ccRCC. This effect would not have been identified if immune infiltrate was assessed using cell density alone, highlighting the importance of including spatial analysis in studies of immune cell infiltration of tumors.

/pdf/spatial-clustering-of-cd68-tumor-associated-macrophages-with-48g0i2d7jw.pdf

Spatial clustering of CD68+ tumor associated macrophages with tumor cells is associated with worse overall survival in metastatic clear cell renal cell carcinoma.

Keywords:

T-cell;
memory T-cell;
immune checkpoint;
PD-1;
TIM3;
LAG-3;
CTLA-4;
tumor-infiltrating lymphocyte;
TIL;
immunotherapy

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cyto.a.22808

OMIP-031: Immunologic checkpoint expression on murine effector and memory T-cell subsets

Due to the pivotal role that dendritic cells (DC) play in eliciting and maintaining functional anti-tumor T cell responses, these APC have been exploited against tumors. DC express several receptors for the Fc portion of IgG (Fcγ receptors) that mediate the internalization of antigen-IgG complexes and promote efficient MHC class I and II restricted antigen presentation. In this study, the efficacy of vaccination with DC pulsed with apoptotic B16 melanoma cells opsonized with an anti-CD44 IgG (B16-CD44) was explored. Immature bone marrow derived DC grown in vitro with IL-4 and GM-CSF were pulsed with B16-CD44. After 48 h of pulsing, maturation of DC was demonstrated by production of IL-12 and upregulation of CD80 and CD40 expression. To test the efficacy of vaccination with DC+B16-CD44, mice were vaccinated subcutaneously Lymphocytes from mice vaccinated with DC+B16-CD44 produced IFN-γ in response to B16 melanoma lysates as well as an MHC class I restricted B16 melanoma-associated peptide, indicating B16 specific CD8 T cell activation. Upon challenge with viable B16 cells, all mice vaccinated with DC alone developed tumor compared to 40% of mice vaccinated with DC+B16-CD44; 60% of the latter mice remained tumor free for at least 8 months. In addition, established lung tumors and distant metastases were significantly reduced in mice treated with DC+B16-CD44. Lastly, delayed growth of established subcutaneous tumors was induced by combination therapy with anti-CD44 antibodies followed by DC injection. This study demonstrates the efficacy of targeting tumor antigens to DC via Fcγ receptors.

/pdf/induction-of-anti-tumor-immunity-by-vaccination-with-175ubfidja.pdf

Induction of anti-tumor immunity by vaccination with dendritic cells pulsed with anti-CD44 IgG opsonized tumor cells.

Continual attempts to stimulate the immune system against malignancies have led to the development of various strategies based on active immunotherapy treatments. Dendritic cells are the most potent antigen presenting cells with the capacity to stimulate naive T cells and induce primary and secondary immune responses. Due to the pivotal role that DC play in eliciting and maintaining functional anti-tumor T cell responses, DC have been exploited as vaccines in an attempt to actively immunize patients. Initial solid tumor clinical trials involving DC-based immunization have shown progress in terms of eliciting T-cell reactivity and mediating tumor regression. These early promising data have led to multiple research endeavors to also employ DC immunotherapy for the treatment of poorly immunogenic malignancies such as breast cancer. Various strategies to load DC with tumor associated antigens in murine models of breast cancer as well as the state of human clinical trials are reviewed.

Dendritic Cell-Based Therapeutics for Breast Cancer

Described herein are methods of cancer immunotherapy, particularly methods of preparing a population of enhanced dendritic cells and methods of treating cancer using the enhanced dendritic cells.

Enhanced dendritic cells for cancer immunotherapy

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