The effect of Wnt/β-catenin signaling on PD-1/PDL-1 axis in HPV-related cervical cancer

Infection with high-risk human papillomavirus(HPV),including HPV-16 and HPV-18,is the main cause of malignancies,such as cervical cancer.Viral oncoproteins encoded by HPV are expressed in HPV-positive cancers and associated with the early cancer stages and the transformation of normal cells.The signaling pathways involved in the transformation of normal cells to cancerous form and the subsequently expressed programmed cell death-ligand 1(PD-L1)on the surface of the transformed cells lead to a disruption in recognition of tumor cells by the immune cell system,including T lymphocytes and dendritic cells which lead to the development of cervical cancer malignancy.These cells also produce modest levels of cytokines during exhaustion,tumor-infiltrating T CD4+cells with high levels of PD-1 and CD39 release considerable quantities of cytokines.The Wnt/β-catenin signaling pathway,which controls the expression of genes involved in the tumor cells’markers,is demonstrated to be one of the most potent cancer stimulants.It leads to the evasion of the tumor cells from immune cell detection and ultimately avoids being recognized by dendritic cells or T-cells.PD-L1,as an inhibitory immune checkpoint,is essential for controlling immune system activity by inhibiting T-cells’inflammatory function.In the present review,we looked into how Wnt/β-catenin affects the expression of PD-L1 and related genes like c-MYC in cancer cells and its role in the development of HPV-induced malignancy.We hypothesized that blocking these pathways could be a potential immunotherapy and cancer prevention method.

Highlights of Miami winter symposium 2015:into the era of immunotherapy

Personalized cancer medicine has seen significant improvements over the past decade. Recent Elsevier conference： Miami winter symposium 2015 （MWS2015） ＂Towards Personalized Cancer Medicine＂ meeting was dedicated to this exciting field, and focused on new progress in personalized drug development and antibody drug against checkpoint pathway. Tais meeting report summarizes the key developments presented and discussed at the meeting, with a focus on immunotherapy, especially on the CTLA-4 and PD-1/PD-L1 pathways. The monoclonal antibody drugs intervening these checkpoint pathways have the potential to play a larger role in personalize medicine within the near future. Here we intended to provide a comprehensive summary about ongoing trends and future perspectives on personalized medicine in cancer therapy.

The immune regulation of PD-1/PDL-1 axis, a potential biomarker in multiple sclerosis

Multiple sclerosis is an autoimmune disease characterised by a chronic inflammation within the central nervous system. In the last ten years, studies on multiple sclerosis have been concentrated on the discovery of new biomarkers of disease and potential therapeutic targets. In chronic infection or in cancer, the immune system response is faulty and maintained in a condition defined as T-cell exhaustion induced by expression of co-inhibitory receptors. The PD-1/PDL-1 pathway is demonstrated to be the main one responsible for promoting T-cell exhaustion, and immunotherapies targeting PD-1 or PDL-1 have shown beneficial clinical outcomes in several tumours and chronic diseases. Contrarily, transcriptional T-cell exhaustion signature and high expression of co-inhibitor receptor PD-1 are associated with favourable prognosis in multiple sclerosis and other autoimmune diseases. Several studies have clearly demonstrated PD-1 has a dual role in immune self-tolerance: to constrain autoreactive T cells in anergic condition and to protect the tissue from the damage caused by the activation of endogenous autoreactive T cells. Consequently, immune checkpoint inhibitor therapies that target inhibitory receptors in cancer cause an exacerbation of autoimmune diseases. This review describes the roles of the PD-1/ PDL-1 pathway in cancer and autoimmune diseases, especially in multiple sclerosis, and how manipulating PD-1 can be a therapeutic approach in multiple sclerosis.

Crosstalk between the B7/CD28 and EGFR pathways:Mechanisms and therapeutic opportunities

Somatic activating mutations in the epidermal growth factor receptor(EGFR)are one of the most common oncogenic drivers in cancers such as non-small-cell lung cancer(NSCLC),metastatic colorectal cancer,glioblastoma,head and neck cancer,pancreatic cancer,and breast cancer.Molecular-targeted agents against EGFR signaling pathways have shown robust clinical efficacy,but patients inevitably experience acquired resistance.Although immune checkpoint inhibitors(ICIs)targeting PD-1/PD-L1 have exhibited durable anti-tumor responses in a subset of patients across multiple cancer types,their efficacy is limited in cancers harboring activating gene alterations of EGFR.Increasing studies have demonstrated that upregulation of new B7/CD28 family members such as B7-H3,B7x and HHLA2,is associated with EGFR signaling and may contribute to resistance to EGFR-targeted therapies by creating an immunosuppressive tumor microenvironment(TME).In this review,we discuss the regulatory effect of EGFR signaling on the PD-1/PD-L1 pathway and new B7/CD28 family member pathways.Understanding these interactions may inform combination therapeutic strategies and potentially overcome the current challenge of resistance to EGFR-targeted therapies.We also summarize clinical data of anti-PD-1/PD-L1 therapies in EGFR-mutated cancers,as well as ongoing clinical trials of combination of EGFR-targeted therapies and anti-PD-1/PD-L1 immunotherapies.

Cancer-cell-biomimetic nanoparticles systemically eliminate hypoxia tumors by synergistic chemotherapy and checkpoint blockade immunotherapy

Checkpoint blockade-based immunotherapy has shown unprecedented effect in cancer treatments,but its clinical implementation has been restricted by the low host antitumor response rate.Recently,chemotherapy is well recognized to activate the immune system during some chemotherapeutics-mediated tumor eradication.The enhancement of immune response during chemotherapy might further improve the therapeutic efficiency through the synergetic mechanism.Herein,a synergistic antitumor platform(designated as BMS/RA@CC-Liposome)was constructed by utilizing CT26 cancer-cell-biomimetic nanoparticles that combined chemotherapeutic drug(RA-V)and PD-1/PD-L1 blockade inhibitor(BMS-202)to remarkably enhance antitumor immunity.In this study,the cyclopeptide RA-V as chemotherapeutic drugs directly killing tumor cells and BMS-202 as anti-PD agents eliciting antitumor immune responses were co-encapsulated in a pH-sensitive nanosystem.To achieve the cell-specific targeting drug delivery,the combination therapy nanosystem was functionalized with cancer cell membrane camouflage.The biomimetic drug delivery system perfectly disguised as endogenous substances,and realized elongated blood circulation due to anti-phagocytosis capability.Moreover,the BMS/RA@CC-Liposome also achieved the selective targeting of CT26 cells by taking advantage of the inherent homologous adhesion property of tumor cells.The in vitro and in vivo experiments revealed that the BMS/RA@CC-Liposome realized PD-1/PD-L1 blockade-induced immune response,RA-V-induced PD-L1 down-regulation and apoptosis in cancer cells.Such a system combining the advantages of chemotherapy and checkpoint blockade-based immunotherapy to create an immunogenic tumor microenvironment systemically,demonstrated improved therapeutic efficacy against hypoxic tumor cells and offers an alternative strategy based on the immunology of the PD-1/PD-L1 pathway.