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Inflammation has accompanied human beings since the emergence of wounds and infections. In the past decades, numerous efforts have been undertaken to explore the potential role of inflammation in cancer, from tumor development, invasion, and metastasis to the resistance of tumors to treatment. Inflammation-targeted agents not only demonstrate the potential to suppress cancer development, but also to improve the efficacy of other therapeutic modalities. In this review, we describe the highly dynamic and complex inflammatory tumor microenvironment, with discussion on key inflammation mediators in cancer including inflammatory cells, inflammatory cytokines, and their downstream intracellular pathways. In addition, we especially address the role of inflammation in cancer development and highlight the action mechanisms of inflammation-targeted therapies in antitumor response. Finally, we summarize the results from both preclinical and clinical studies up to date to illustrate the translation potential of inflammation-targeted therapies. [ABSTRACT FROM AUTHOR]

Initially understood for its physiological maintenance of self-tolerance, the immune checkpoint molecule has recently been recognized as a promising anti-cancer target. There has been considerable interest in the biology and the action mechanism of the immune checkpoint therapy, and their incorporation with other therapeutic regimens. Recently the small-molecule inhibitor (SMI) has been identified as an attractive combination partner for immune checkpoint inhibitors (ICIs) and is becoming a novel direction for the field of combination drug design. In this review, we provide a systematic discussion of the biology and function of major immune checkpoint molecules, and their interactions with corresponding targeting agents. With both preclinical studies and clinical trials, we especially highlight the ICI + SMI combination, with its recent advances as well as its application challenges. [ABSTRACT FROM AUTHOR]

The Human Epidermal Growth Factor Receptor family is composed of 4 structurally related receptor tyrosine kinases that are involved in many human cancers. The efficacy and safety of HER inhibitors have been compared in a wide range of clinical trials, suggesting the superior inhibitory ability of multiple- HER-targeting blockade compared with single receptor antagonists. However, many patients are currently resistant to current therapeutic treatment and novel strategies are warranted to conquer the resistance. Thus, we performed a critical review to summarize the molecular involvement of HER family receptors in tumour progression, recent anti-HER drug development based on clinical trials, and the potential resistance mechanisms of anti-HER therapy. [ABSTRACT FROM AUTHOR]

Regulating natural killer (NK) cell responses in hematological malignancies largely depend on molecular interactions between killer cell immunoglobulin-like receptors (KIR) and human leukocyte antigen (HLA) class I ligands. The goal of the current study was to examine the key functions of KIR genes, gene combinations of KIR-HLA, and KIR genotypes in genetic predisposition to aplastic anemia (AA). Herein, the genotyping of 16 KIR genes and HLA-A, -B, and -C ligands were performed in 72 AA patients and 150 healthy controls using PCR evaluations with sequence-specific primers using standard assays. According to the obtained results, AA patients had an increased incidence of activating KIR and KIR2DS4 (P = 0.465 × 10−4, Pc = 0.837 × 10−3, OR = 20.81, 95% CI = 2.786–155.5) compared to controls. KIR/HLA class I ligand profile KIR2DS4/C1 (P = 0.350 × 10−4, Pc = 0.630 × 10−3, OR = 8.944, 95% CI = 2.667–29.993) was significantly elevated in AA patients compared to healthy controls. Genotype AA1 (P = 0.003, OR = 2.351, 95% CI = 1.325–4.172) were increased, and AA195 (P = 0.006, OR = 0.060, 95% CI = 0.004–1.023) was decreased among AA cases compared to controls. Our findings indicated that KIR2DS4 may play a role in the pathogenesis of AA. This study revealed the contribution of KIR genes in the etiology of AA cases. [ABSTRACT FROM AUTHOR]

Chemokine C-X-C motif ligand 13 (CXCL13), originally identified as a B-cell chemokine, plays an important role in the immune system. The interaction between CXCL13 and its receptor, the G-protein coupled receptor (GPCR) CXCR5, builds a signaling network that regulates not only normal organisms but also the development of many diseases. However, the precise action mechanism remains unclear. In this review, we discussed the functional mechanisms of the CXCL13-CXCR5 axis under normal conditions, with special focus on its association with diseases. For certain refractory diseases, we emphasize the diagnostic and therapeutic role of CXCL13-CXCR5 axis. [ABSTRACT FROM AUTHOR]

In recent decades, cancer immunotherapy has demonstrated considerable clinical advantages in cancer therapy. Particularly, the use of immunological gene therapy continues to grow in this field. Macrophage Inflammatory Protein 3 Beta (MIP-3β) has emerged as a potential immunomodulator for anti-cancer treatments by enhancing the interaction among immune responses. In this study, we demonstrate an innovative targeted gene delivery system based on a self-assembly technique with 1,2-Dioleoyl-3-trimethylammonium-propane (DOTAP), Methoxy poly(ethylene glycol)-poly(lactide) (MPEG-PLA), and folic acid modified poly(ethylene glycol)-poly(ε-caprolactone) (FA-PEG-PCL) (FDMCA). Results showed that the expression of MIP-3β was up-regulated in cancer cells following the transfection with FDMCA-pMIP-3β, in comparison with cells transfected with DMCA-pMIP-3β. The supernatants collected from cancer cells transfected with FDMCA-pMIP-3β and DMCA-pMIP-3β both instigate dendritic cell maturation, M1 polarisation of macrophages, activation and presentation of cytotoxicity in lymphocytes. Moreover, tumor growth and metastasis were markedly inhibited following the administration of the FDMCA-pMIP-3β complex in both subcutaneous and pulmonary metastasis mice models, which is attributed to reduced angiogenesis, enhanced cancer cell apoptosis, and suppressed proliferation by activation of the immune system. Our study suggests that the MIP-3β plasmid and FDMCA complex provide a new approach for the treatment of breast cancer. Diagram of process of the FDMCA transfection and immune activation Cancer cells were transfected with FDMCA-pMIP-3β and secreted MIP-3β factors to induce immune activation, which prompted lymphocyte proliferation and DCs maturation, as well as inhibition of macrophage polarisation to M2. Image 1 [ABSTRACT FROM AUTHOR]

Transforming growth factor β (TGF-β) has long been identified with its intensive involvement in early embryonic development and organogenesis, immune supervision, tissue repair, and adult homeostasis. The role of TGF-β in fibrosis and cancer is complex and sometimes even contradictory, exhibiting either inhibitory or promoting effects depending on the stage of the disease. Under pathological conditions, overexpressed TGF-β causes epithelial-mesenchymal transition (EMT), extracellular matrix (ECM) deposition, cancer-associated fibroblast (CAF) formation, which leads to fibrotic disease, and cancer. Given the critical role of TGF-β and its downstream molecules in the progression of fibrosis and cancers, therapeutics targeting TGF-β signaling appears to be a promising strategy. However, due to potential systemic cytotoxicity, the development of TGF-β therapeutics has lagged. In this review, we summarized the biological process of TGF-β, with its dual role in fibrosis and tumorigenesis, and the clinical application of TGF-β-targeting therapies. [ABSTRACT FROM AUTHOR]

Research on tumor immunotherapy has made tremendous progress in the past decades, with numerous studies entering the clinical evaluation. The cancer vaccine is considered a promising therapeutic strategy in the immunotherapy of solid tumors. Cancer vaccine stimulates anti-tumor immunity with tumor antigens, which could be delivered in the form of whole cells, peptides, nucleic acids, etc. Ideal cancer vaccines could overcome the immune suppression in tumors and induce both humoral immunity and cellular immunity. In this review, we introduced the working mechanism of cancer vaccines and summarized four platforms for cancer vaccine development. We also highlighted the clinical research progress of the cancer vaccines, especially focusing on their clinical application and therapeutic efficacy, which might hopefully facilitate the future design of the cancer vaccine. [ABSTRACT FROM AUTHOR]

Background: Hepatic stellate cell (HSC) activation plays a pivotal role in hepatic inflammation and liver fibrosis. TLR4 pathway activation has been reported to be involved in mice liver fibrosis induced by hepatitis virus infection, alcohol abuse, biliary ligation, carbon tetrachloride 4 treatment, and Schistosoma japonicum (Sj) infection. The effect and mechanisms of the cyclooxygenase 2 (COX2)/prostanoid E2 (PGE2) axis on liver fibrosis induced by Sj are still unclear. Methods: Mice liver fibrosis were induced by cutaneous infection of Sj cercariae. COX-2 inhibitor, NS398 were injected from week 5 to week 7, while TLR4 inhibitor TAK242 were injected from week 4 to week 8 post Sj infection. Human HSCs line, LX-2 cells were cultured and exposed to LPS or synthetic PGE2, or pretreated by TAK242, TLR4-siRNA or NS398. Liver tissue and serum or in vitro cultured cell lysaste were collected at indicated time courses for exploring the relationship between TLR4 and COX2-PGE2 axis through qPCR, western blot, immunohistochemical assay, ect. One-way analysis of variance among multiple groups followed by Uncorrected Fisher's LSD-t test or paired comparisons through t test were performed to tell the statistical differences. Results: This study investigated the link between the COX2/PGE2 axis and TLR4 signaling in the induction of liver fibrogenesis in mice during Sj infection and in vitro culture of HSC strain-LX-2. The COX2/PGE2 axis was positively associated with Sj-induced liver fibrosis. TLR4 pathway activation stimulated the COX2/PGE2 axis in Sj-infected mice and in lipopolysaccharide (LPS)-exposed cultured HSCs. Synthetic PGE2 activated cultured HSCs through upregulation of alpha smooth muscle actin (α-SMA) expression. In LPS-triggered HSCs, NS398, a COX2 inhibitor, led to suppression of PGE2 synthesis and reduced expression of α-SMA and type I collagen (COL I). Conclusions: These results indicate firstly the positive association of the COX2/PGE2 axis with liver fibrosis induced by Sj infection. TLR4 signaling may at least partially control the COX2/PGE2 axis in Sj-infected mice liver and in vitro cultured HSCs. The COX2/PGE2-EP2/EP4 axis might be a good drug target against liver fibrosis induced by Sj infection. [ABSTRACT FROM AUTHOR]

Background: Hepatic stellate cell (HSC) activation plays a pivotal role in hepatic inflammation and liver fibrosis. TLR4 pathway activation has been reported to be involved in mice liver fibrosis induced by hepatitis virus infection, alcohol abuse, biliary ligation, carbon tetrachloride 4 treatment, and Schistosoma japonicum (Sj) infection. The effect and mechanisms of the cyclooxygenase 2 (COX2)/prostanoid E2 (PGE2) axis on liver fibrosis induced by Sj are still unclear. Methods: Mice liver fibrosis were induced by cutaneous infection of Sj cercariae. COX-2 inhibitor, NS398 were injected from week 5 to week 7, while TLR4 inhibitor TAK242 were injected from week 4 to week 8 post Sj infection. Human HSCs line, LX-2 cells were cultured and exposed to LPS or synthetic PGE2, or pretreated by TAK242, TLR4-siRNA or NS398. Liver tissue and serum or in vitro cultured cell lysaste were collected at indicated time courses for exploring the relationship between TLR4 and COX2-PGE2 axis through qPCR, western blot, immunohistochemical assay, ect. One-way analysis of variance among multiple groups followed by Uncorrected Fisher's LSD-t test or paired comparisons through t test were performed to tell the statistical differences. Results: This study investigated the link between the COX2/PGE2 axis and TLR4 signaling in the induction of liver fibrogenesis in mice during Sj infection and in vitro culture of HSC strain-LX-2. The COX2/PGE2 axis was positively associated with Sj-induced liver fibrosis. TLR4 pathway activation stimulated the COX2/PGE2 axis in Sj-infected mice and in lipopolysaccharide (LPS)-exposed cultured HSCs. Synthetic PGE2 activated cultured HSCs through upregulation of alpha smooth muscle actin (α-SMA) expression. In LPS-triggered HSCs, NS398, a COX2 inhibitor, led to suppression of PGE2 synthesis and reduced expression of α-SMA and type I collagen (COL I). Conclusions: These results indicate firstly the positive association of the COX2/PGE2 axis with liver fibrosis induced by Sj infection. TLR4 signaling may at least partially control the COX2/PGE2 axis in Sj-infected mice liver and in vitro cultured HSCs. The COX2/PGE2-EP2/EP4 axis might be a good drug target against liver fibrosis induced by Sj infection. [ABSTRACT FROM AUTHOR]

γδ‐T cells are innate‐like T cells with dual antitumor activities. They can directly eradicate tumor cells and function as immunostimulatory cells to promote antitumor immunity. Previous studies have demonstrated that small extracellular vesicles (EVs) derived from γδ‐T cells (γδ‐T‐EVs) inherited the dual antitumor activities from their parental cells. However, it remains unknown whether γδ‐T‐EVs can be designed as tumors vaccine to improve therapeutic efficacy. Here, we found that γδ‐T‐EVs had immune adjuvant effects on antigen‐presenting cells, as revealed by enhanced expression of antigen‐presenting and co‐stimulatory molecules, secretion of pro‐inflammatory cytokines and antigen‐presenting ability of DCs after γδ‐T‐EVs treatment. The γδ‐T‐EVs‐based vaccine was designed by loading tumor‐associated antigens (TAAs) into γδ‐T‐EVs. Compared with γδ‐T‐EVs, the γδ‐T‐EVs‐based vaccine effectively promoted more tumor‐specific T‐cell responses. In addition, the vaccine regimen preserved direct antitumor effects and induced tumor cell apoptosis. Interestingly, the allogeneic γδ‐T‐EVs‐based vaccine showed comparable preventive and therapeutic antitumor effects to their autologous counterparts, indicating a better way of centralization and standardization in clinical practice. Furthermore, the allogeneic γδ‐T‐EVs‐based vaccine displayed advantages over the DC‐EVs‐based vaccine through their dual antitumor activities. This study provides a proof‐of‐concept for using the allogeneic γδ‐T‐EVs‐based vaccine in cancer control. [ABSTRACT FROM AUTHOR]

Background: To estimate the prognostic value of inflammatory markers in patients with laryngeal squamous cell carcinoma (LSCC).Methods: A total of 361 resected LSCC patients were included. The preoperative and postoperative neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), alkaline phosphatase (ALP) and l actate dehydrogenase (LDH) were assessed. The Kaplan-Meier survival analysis and Cox regression analysis were conducted on overall survival (OS) and progression-free survival (PFS).Results: Both Kaplan-Meier analysis and univariate analysis demonstrated significant prognostic value of preoperative and postoperative NLR, PLR and MLR. However, only preoperative ALP was predictive of OS and PFS, and LDH failed to be predictor of OS and PFS. The multivariate analysis showed that preoperative NLR (OS: HR = 1.64, 95%CI: 1.06-2.54, p = 0.026; PFS: HR = 1.52, 95%CI: 1.04-2.23, p = 0.029) and postoperative MLR (OS: HR = 2.02, 95%CI: 1.29-3.14, p = 0.002; PFS: HR = 1.57, 95%CI: 1.05-2.34, p = 0.026) were independently related with survival.Conclusions: The elevated preoperative NLR, PLR, MLR and ALP were significantly associated with worse survival and cancer progression. The preoperative NLR and postoperative MLR might be independent prognostic markers of OS and PFS in LSCC patients undergoing surgical resection. [ABSTRACT FROM AUTHOR]