Recent advances in the field of anti-cancer immunotherapy

AbstractBackgroundThe main goal of anti-cancer therapy is to specifically inhibit the malignant activity of cancer cells, while leaving healthy cells unaffected. As such, for every proposed therapy, it is important to keep in mind the therapeutic index — the ratio of the toxic dose over the therapeutic dose. The use of immunotherapy has allowed a means to both specifically block protein–protein interaction and deliver cytotoxic events to a tumor-specific antigen.Review scopeIt is the objective of this review to give an overview on current immunotherapy treatment for cancers using monoclonal antibodies. We demonstrate three exciting targets for immunotherapy, TNF-α Converting Enzyme (TACE), Cathepsin S and Urokinase Plasmogen Activator and go over the advances made with one of the most used monoclonal antibodies in cancer therapy, Rituximab; as well as Herceptin, which is used for breast cancer therapy. Furthermore, we touch on other venues of immunotherapy, such as adaptive cell transfer, the use of nucleic acids and the use of dendritic cells. Finally, we summarize some ongoing studies that spell tentative advancements for anti-cancer immunotherapy.General significanceImmunotherapy is at the forefront of anti-cancer therapies, allying both a high degree of specificity to general high effectiveness and fewer side-effects

The function and regulation of PD-L1 in immunotherapy

PD-L1, also known as B7-H1, is a type I transmembrane protein, which is expressed in different kinds of tumor cells. It is correlated with poor clinical outcome of patients with various types of tumors. PD-L1 can regulate tumor microenvironment or tumor related immune response through suppressing T cell or NK cell mediated immune response. PD-L1 expression is regulated by various cytokines, such as LPS, GM-CSF, IL-4, TGF-β, TNF-α. PD-1 and PD-L1 are the members of B7 and CD28 superfamily, respectively. The B7/CD28 interaction plays a central role in immune tolerance. PD-L1 can bind to PD-1, which leads to the suppression of lymphocyte activation and apoptosis of lymphocytes. Anti-PD-L1 therapy is one of the immunotherapies to treat cancer (especially solid tumor). PD-L1 expression may be associated with efficacy of anti PD-1/PD-L1 therapy. In this review, we will focus on the regulation mechanism of PD-L1 expression, and describe the role of PD-1/PD-L1 binding on the anti-PD-1/PD-L1 therapy

A Review on Bradykinin-Related Peptides Isolated from Amphibian Skin Secretion

Amphibian skin secretion has great potential for drug discovery and contributes hundreds of bioactive peptides including bradykinin-related peptides (BRPs). More than 50 BRPs have been reported in the last two decades arising from the skin secretion of amphibian species. They belong to the families Ascaphidae (1 species), Bombinatoridae (3 species), Hylidae (9 speices) and Ranidae (25 species). This paper presents the diversity of structural characteristics of BRPs with N-terminal, C-terminal extension and amino acid substitution. The further comparison of cDNA-encoded prepropeptides between the different species and families demonstrated that there are various forms of kininogen precursors to release BRPs and they constitute important evidence in amphibian evolution. The pharmacological activities of isolated BRPs exhibited unclear structure–function relationships, and therefore the scope for drug discovery and development is limited. However, their diversity shows new insights into biotechnological applications and, as a result, comprehensive and systematic studies of the physiological and pharmacological activities of BRPs from amphibian skin secretion are needed in the future

The prognostic significance of PD-L1 in bladder cancer

published_or_final_versio

The Prognostic Significance of Combining VEGFA, FLT1 and KDR mRNA Expressions in Brain Tumors

© 2015 Ivyspring International Publisher. Reproduction is permitted for personal, noncommercial use, provided that the article is in whole, unmodified, and properly cited. Se

The significance of combining VEGFA, FLT1, and KDR expressions in colon cancer patient prognosis and predicting response to bevacizumab

Targeting angiogenesis through inhibition of the vascular endothelial growth factor (VEGF) pathway has been successful in the treatment of late stage colorectal cancer. However, not all patients benefit from inhibition of VEGF. Ras status is a powerful biomarker for response to anti-epidermal growth factor receptor therapy; however, an appropriate biomarker for response to anti-VEGF therapy is yet to be identified. VEGF and its receptors, FLT1 and KDR, play a crucial role in colon cancer progression; individually, these factors have been shown to be prognostic in colon cancer; however, expression of none of these factors alone was predictive of tumor response to anti-VEGF therapy. In the present study, we analyzed the expression levels of VEGFA, FLT1, and KDR in two independent colon cancer datasets and found that high expression levels of all three factors afforded a very poor prognosis. The observation was further confirmed in another independent colon cancer dataset, wherein high levels of expression of this three-gene signature was predictive of poor prognosis in patients with proficient mismatch repair a wild-type KRas status, or mutant p53 status. Most importantly, this signature also predicted tumor response to bevacizumab, an antibody targeting VEGFA, in a cohort of bevacizumab-treated patients. Since bevacizumab has been proven to be an important drug in the treatment of advanced stage colon cancer, our results suggest that the three-gene signature approach is valuable in terms of its prognostic value, and that it should be further evaluated in a prospective clinical trial to investigate its predictive value to anti-VEGF treatment

Regulation of IFN-γ-mediated PD-L1 expression by MYC in colorectal cancer with wild-type KRAS and TP53 and its clinical implications

Introduction: In the tumor microenvironment, interferon gamma (IFN-γ) secreted by tumor infiltrating lymphocytes can upregulate programmed cell death 1 ligand 1 (PD-L1) expression in many cancers. The present study evaluated the expression of PD-L1 in selected colorectal cancer cell lines with IFN-γ treatment and explored the correlation between programmed cell death 1 ligand 1 expression and KRAS/TP53 mutation status.Methods: The selected colorectal cancer cell lines had known KRAS mutations or TP53 mutations. TCGA data analysis were used to investigate the correlation between overall survival of patient with anti-PD-1/PD-L1 immunotherapy and KRAS/TP53 mutation status. Besides, the correlation between PD-L1 expression and KRAS/TP53 mutation status were also investigated by using TCGA data analysis. In vitro experiments were used to explore the mechanism underlying KRAS- and TP53-related PD-L1 expression.Results: Firstly, TCGA data analysis for gene expression and overall survival and an in vitro study revealed that the wild-type KRAS/TP53 cell lines exhibited hyperresponsiveness to interferon gamma exposure and correlated with better survival in patients receiving anti-PD-1/PD-L1 treatment. Secondly, experimental data revealed that interferon gamma induced the upregulation of programmed cell death 1 ligand 1 mainly through regulating MYC in wild-type KRAS and TP53 colorectal cancers.Discussion: Our findings revealed that the response to anti-PD-1/PD-L1 cancer immunotherapy frequently happened in wild-type KRAS and TP53 colorectal cancers, which were also found to show higher programmed cell death 1 ligand 1 expression. Our results indicate that the wild-type KRAS/TP53 colorectal cancer cell lines may respond better to interferon gamma treatment, which causes increased programmed cell death 1 ligand 1 expression and may be a mechanism underlying the better responses to anti-PD-1/PD-L1 therapies in wild-type KRAS and wild-type TP53 colorectal cancer. Furthermore, the experimental results suggest that interferon gamma regulated programmed cell death 1 ligand 1 expression through the regulation of MYC, which may further affect the response to PD-1/PD-L1 cancer immunotherapy. These results suggest a novel potential treatment strategy for enhancing the efficacy of PD-1/PD-L1 blockade immunotherapy in most colorectal cancer patients