Chinese expert consensus recommendations for the administration of immune checkpoint inhibitors to special cancer patient populations.

Immune checkpoint inhibitors (ICIs) targeting programmed cell death 1, programmed cell death ligand 1, and cytotoxic T lymphocyte-associated antigen-4 have shown significantly durable clinical benefits and tolerable toxicities and have improved the survival of patients with various types of cancer. Since 2018, the National Medical Products Administration of China has approved 17 ICIs as the standard treatment for certain advanced or metastatic solid tumors. As ICIs represent a broad-spectrum antitumor strategy, the populations eligible for cancer immunotherapy are rapidly expanding. However, the clinical applications of ICIs in cancer patient populations with special issues, a term that refers to complex subgroups of patients with comorbidities, special clinical conditions, or concomitant medications who are routinely excluded from prospective clinical trials of ICIs or are underrepresented in these trials, represent a great real-world challenge. Although the Chinese Society of Clinical Oncology (CSCO) has provided recommendations for screening before the use of ICIs in special populations, the recommendations for full-course management remain insufficient. The CSCO Expert Committee on Immunotherapy organized leading medical oncology and multidisciplinary experts to develop a consensus that will serve as an important reference for clinicians to guide the proper application of ICIs in special patient populations. This article is a translation of a study first published in Chinese in The Chinese Clinical Oncology (ISSN 1009-0460, CN 32-1577/R) in May 2022 (27(5):442-454). The publisher of the original paper has provided written confirmation of permission to publish this translation in Therapeutic Advances in Medical Oncology.

Case report: Cryoablation as a novel bridging strategy prior to CAR-T cell therapy for B cell malignancies with bulky disease.

Chimeric antigen receptor (CAR) T-cell therapy has emerged as a powerful immunotherapy in relapsed/refractory (R/R) hematological malignancies, especially in R/R B-cell acute lymphocytic leukemia (B-ALL), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM). To prevent disease progression and reduce tumor burden during CAR-T cell manufacturing, bridging therapies prior to CAR-T cell infusion are crucial. At present, it has been demonstrated that targeted therapy, radiotherapy and autologous stem cell transplantation (ASCT) could serve as effective bridging strategies. However, whether cryoablation could serve as a novel bridging strategy is unknown. In this paper, we report 2 cases of R/R B cell malignancies with bulky disease that were successfully treated with a combination of cryoablation and CAR-T cell therapy. Patient 1 was a 65-year-old female who was diagnosed with R/R MM with extramedullary disease (EMD). She was enrolled in the anti-BCMA CAR-T cell clinical trial. Patient 2 was a 70-year-old man who presented with a subcutaneous mass in the right anterior thigh and was diagnosed with primary cutaneous diffuse large B cell lymphoma, leg type (PCLBCL-LT) 1 year ago. He failed multiline chemotherapies as well as radiotherapy. Thus, he requested anti-CD19 CAR-T cell therapy. Unfortunately, they all experienced local progression during CAR-T cell manufacturing. To rapidly achieve local tumor control and reduce tumor burden, they both received cryoablation as a bridging therapy. Patient 1 achieved a very good partial response (VGPR) 1 month after CAR-T cell infusion, and patient 2 achieved a partial response (PR) 1 month after CAR-T cell infusion. In addition, adverse effects were tolerable and manageable. Our study demonstrated the favorable safety and efficacy of combination therapy with cryoablation and CAR-T cell therapy for the first time, and it also indicates that cryoablation could serve as a novel therapeutic strategy for local tumor control in B cell malignancies.

Idecabtagene vicleucel for relapsed/refractory multiple myeloma: a review of recent advances.

The introduction of new classes of drugs for the treatment of multiple myeloma (MM) in the past 2 decades, such as proteasome inhibitors, immunomodulators and anti-CD38 monoclonal antibodies, coupled with autologous stem cell transplantation, has approximately doubled the 5-year survival rate of MM patients. However, the patients eventually relapse and/or become resistant to the drugs and treatment. The recent emergence of anti-B-cell maturation antigen (BCMA) therapies, especially chimeric antigen receptor T-cell (CAR-T) immunotherapy targeting BCMA, holds great prospect in MM treatment. In this article, we review in detail the advances of idecabtagene vicleucel (ide-cel, bb-2121), the first CAR-T therapy targeting BCMA for treating relapse or refractory MM approved by the U.S. Food and Drug Administration (FDA) in 2021, including the preclinical study and phase I and II clinical trials. Also, it is predicted in this review that despite its amazing clinical efficacy and relatively lower toxicity, a lot of challenges and unsolved problems for ide-cel therapy remain in the way ahead.

Features of Cytokine Storm Identified by Distinguishing Clinical Manifestations in COVID-19.

Coronavirus disease 2019 (COVID-19) is caused by a new coronavirus, namely severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is currently spreading all over the world. In this paper, we developed a practical model for identifying the features of cytokine storm, which is common in acute infectious diseases and harmful manifestation of COVID-19, by distinguishing major and minor clinical events. This model is particularly suitable for identifying febrile and infectious diseases like COVID-19. Based on this model, features of cytokine storm and pathogenesis of COVID-19 have been proposed to be a consequence of the disequilibrated cytokine network resulting from increased biological activity of transforming growth factor-ß (TGF-ß), which induces certain clinical manifestations such as fatigue, fever, dry cough, pneumonia, abatement and losing of olfactory, and taste senses in some patients. Research and clarification of the pathogenesis of COVID-19 will contribute to precision treatment. Various anti-TGF-ß therapies may be explored as potential COVID-19 treatment. This novel model will be helpful in reducing the widespread mortality of COVID-19.

WW45 inhibits breast cancer cell proliferation by the Hedgehog signaling pathway.

WW45 is a recently-discovered tumor suppressor gene. Overexpression of WW45 was found to significantly weaken proliferation and colony formation in a human breast cancer cell line, but the molecular mechanism of WW45's inhibitiory effect on proliferation was uncertain. It is a key transcription factor of the Hedgehog signaling pathway. In particular, the mechanism of Gli1's upstream proteins in regulating Gli1's nuclear import was not clear.We collected different breast cancer cell lines and detected WW45 and Gli1 expression by western blot. Gli1 expression was detected after WW45 was overexpressed in breast cancer cells. Gli1 and WW45 were transfected into breast cancer cells, and co-immunoprecipitation was used to detect whether the two proteins had physical interaction. We confirmed Gli1 blocks WW45-induced growth inhibition and colony formation in ZR-75-30 cells through cell functional experiments. Expression of WW45 negatively correlated with Gli1 expression in breast cancer cells. WW45 affected Gli1 intracellular localization though ww-PPxY/PsP interaction. Gli1 blocked WW45-induced growth inhibition and colony formation in ZR-75-30 cells. Our results strongly suggest that expression of WW45 negatively correlates with Gli1 expression in breast cancer cells. direct physical interaction occurred between WW45 and Gli1, and WW45 affected Gli1 intracellular localization though WW-PPxY/PsP interaction. Furthermore, Gli1 blocked WW45-induced breast cancer cell growth inhibition.

miR-1254 induced by NESG1 inactivates HDGF/DDX5-stimulated nuclear translocation of ß-catenin and suppresses NPC metastasis.

Nasopharyngeal carcinoma (NPC) is one of the most common malignant tumors in Chinese and other Southeast Asians. We aimed to explore the precise mechanism for NESG1 in NPC for understanding the pathogenesis of NPC. Transwell, Boyden assays, and wounding healing were respectively performed for cell metastasis. The microRNA (miRNA) microarray and luciferase reporter assays were designed to clarify NESG1-modulated miRNAs and miR-1254-targeted protein. Western blotting assays examined the pathways regulated by miR-1254, the (Hepatoma-Derived Growth Factor) HDGF/DDX5 complex, and NESG1. The chromatin immunoprecipitation (ChIP), electrophoretic mobility shift assay (EMSA), and co-immunoprecipitation (coIP) assays were used to explore the DNA-protein complex and protein-protein complex. NESG1 suppressed NPC migration and invasion via Wnt/ß-catenin signaling. Further, miR-1254 was confirmed as a positive downstream modulator of NESG1 reducing metastatic abilities of NPC cells in vivo and in vitro. Transduction of HDGF significantly restored cell migration and invasion ability in miR-1254-overexpressing NPC cells. In clinical samples, miR-1254 expression was negatively correlated with HDGF and positively correlated with NESG1 expression. miR-1254 acts as an independent prognostic factor for NPC, which was induced by NESG1 to suppress NPC metastasis via inactivating Wnt/ß-catenin pathway and its downstream EMT signals.

Increased PA2G4 Expression Is an Unfavorable Factor in Nasopharyngeal Carcinoma.

PA2G4 plays a dual role in tumors. However, the correlation of its expression with clinical feature and prognosis has never been reported in nasopharyngeal carcinoma (NPC). Using immunohistochemical staining, we examined PA2G4 protein level in clinicopathologically characterized 201 NPC cases (138 male and 63 female) with age ranging from 21 to 83 years and 45 nasopharyngeal (NP) tissues. Statistical methods were used to assess the difference in PA2G4 expression and its relationship with clinical parameters and prognosis in NPC. Immunohistochemical analysis showed that the protein expression of PA2G4 examined in NPC tissues was higher than that in the nasopharyngeal tissues (P=0.005). In addition, high levels of PA2G4 protein were positively correlated with tumor size (T classification) (P<0.001), the status of lymph node metastasis (N classification) (P<0.001), distant metastasis (P=0.029), and clinical stage (P<0.001) of NPC patients. Patients with higher PA2G4 expression had a significantly shorter overall survival time than did patients with low PA2G4 expression. Stratified analysis indicated that high expression of PA2G4 showed the inversed survival time in clinical stages III-IV, but not stages I-II. Finally, multivariate analysis suggested that the level of PA2G4 expression was an independent prognostic indicator (P<0.001) for the survival of patients with NPC. Elevated protein expression of PA2G4 was significantly shown, which plays an unfavorable outcome for NPC patient survival.

VPS33B modulates c-Myc/p53/miR-192-3p to target CCNB1 suppressing the growth of non-small cell lung cancer.

VPS33B is reported to be a tumor suppressor in hepatocellular carcinoma, nasopharyngeal carcinoma, colon cancer, and lung adenocarcinoma. Here, we observed that reduced VPS33B protein level was an unfavorable factor that promoted the pathogenesis of non-small cell lung cancer (NSCLC) in clinical specimens. We achieved lentivirus-mediated stable overexpression of VPS33B in NSCLC cells. Increased VPS33B reduced cell cycle transition and cell proliferation of NSCLC cells in vivo and in vitro. Knocking down VPS33B restored cell growth. Mechanism analysis indicated that miR-192-3p was induced by VPS33B and acted as a tumor suppressor of cell growth in NSCLC. Further, c-Myc or p53 was identified as a transcription factor that bound to the miR-192-3p promoter and regulated its expression. miR-192-3p directly targeted cell cycle-promoted factor CCNB1 and suppressed NSCLC cell growth. VPS33B modulated c-Myc/p53/miR-192-3p signaling to target CCNB1 by reducing activation of the Ras/ERK pathway. Our study reveals a novel molecular basis for VPS33B as a tumor suppressor to participate in the pathogenesis of NSCLC.

ARRB2 promotes colorectal cancer growth through triggering WTAP.

Colorectal cancer (CRC) is one of the most lethal cancers worldwide. The expression of ß-arrestin2 (ß-Arr2, ARRB2) in CRC has been well investigated; however, its exact mechanism causing the cancer progression remains unclear. In this study, we discovered that the expression level of ARRB2 was significantly upregulated in CRC as compared to the normal tissues by employing the Cancer Genome Atlas (TCGA) data, western blot analysis, and immunohistochemistry. Furthermore, the level of ARRB2 was correlated with the patients' overall survival by Kaplan-Meier analysis. The higher expression of ARRB2 promoted CRC cell growth, enhanced the cell motility, and blocked cell apoptosis, which is crucial for tumor growth. Lastly, the suppression of ARRB2 expression was enough to attenuate the progression of CRC induced by azoxymethane/dextran sodium sulfate. Interestingly, we also found that the knockdown of ARRB2 decreased several cancer pathways mediated by the expression of Wilms tumor 1 associated protein (WTAP), which led to the inhibition of cell proliferation and migration. Altogether, our results demonstrated that ARRB2 promoted the growth and migration of CRC cells by regulating the WTAP expression.

EFTUD2 maintains the survival of tumor cells and promotes hepatocellular carcinoma progression via the activation of STAT3.

Elongation factor Tu GTP binding domain containing 2 (EFTUD2), a spliceosomal GTPase, plays a pivotal role in multiple organ development and innate immune. It has been reported that EFTUD2 is a new host factor with activity against HCV infection. However, the role of EFTUD2 in solid tumors, including hepatocellular carcinoma (HCC), remains unexplored. In this study, we investigated the molecular function of EFTUD2 in HCC. Data from The Cancer Genome Atlas (TCGA) indicated an upregulation of EFTUD2 in HCC tissues compared to that in nontumor liver tissues. Immunohistochemical analysis performed on two independent HCC cohorts confirmed the upregulation of EFTUD2 in HCC tissues and further suggested that a high level of EFTUD2 expression predicted shorter overall and recurrence-free survival in HCC patients. Functional studies suggested that siRNA interference with EFTUD2 expression significantly suppressed cell viability, blocked cell cycle progression, facilitated tumor cell apoptosis, and inhibited metastasis, while the enhancement of EFTUD2 expression promoted the proliferation and migration of HCC cells both in vitro and in vivo. Surprisingly, we also found that the stable knockdown of EFTUD2 expression via lentivirus infection was lethal for HCC cells. This finding suggested that EFTUD2 was essential for maintaining the survival of HCC cells. Mechanistically, RNA sequencing and gene set enrichment analysis (GSEA) suggested that the gene sets of epithelial-mesenchymal transition (EMT) and the JAK/STAT3 pathway were enriched in EFTUD2-overexpressing cells. Further verification indicated that EFTUD2-overexpressing cells exhibited an EMT-like phenotype and had enhanced STAT3 activation, while the STAT3 inhibitor S3I-201 partially blocked these pro-malignant effects of EFTUD2 overexpression. In summary, we report EFTUD2 as a novel oncogene that helps to maintain the survival of HCC cells and promotes HCC progression through the activation of STAT3. The high level of expression of EFTUD2 in HCC tissues indicates shorter overall and recurrence-free survival in HCC patients.

Silencing MYH9 blocks HBx-induced GSK3ß ubiquitination and degradation to inhibit tumor stemness in hepatocellular carcinoma.

MYH9 has dual functions in tumors. However, its role in inducing tumor stemness in hepatocellular carcinoma (HCC) is not yet determined. Here, we found that MYH9 is an effective promoter of tumor stemness that facilitates hepatocellular carcinoma pathogenesis. Importantly, targeting MYH9 remarkably improved the survival of hepatocellular carcinoma-bearing mice and promoted sorafenib sensitivity of hepatocellular carcinoma cells in vivo. Mechanistic analysis suggested that MYH9 interacted with GSK3ß and reduced its protein expression by ubiquitin-mediated degradation, which therefore dysregulated the ß-catenin destruction complex and induced the downstream tumor stemness phenotype, epithelial-mesenchymal transition, and c-Jun signaling in HCC. C-Jun transcriptionally stimulated MYH9 expression and formed an MYH9/GSK3ß/ß-catenin/c-Jun feedback loop. X protein is a hepatitis B virus (HBV)-encoded key oncogenic protein that promotes HCC pathogenesis. Interestingly, we observed that HBV X protein (HBX) interacted with MYH9 and induced its expression by modulating GSK3ß/ß-catenin/c-Jun signaling. Targeting MYH9 blocked HBX-induced GSK3ß ubiquitination to activate the ß-catenin destruction complex and suppressed cancer stemness and EMT. Based on TCGA database analysis, MYH9 was found to be elevated and conferred poor prognosis for hepatocellular carcinoma patients. In clinical samples, high MYH9 expression levels predicted poor prognosis of hepatocellular carcinoma patients. These findings identify the suppression of MYH9 as an alternative approach for the effective eradication of CSC properties to inhibit cancer migration, invasion, growth, and sorafenib resistance in HCC patients. Our study demonstrated that MYH9 is a crucial therapeutic target in HCC.

NCOA5 deficiency promotes a unique liver protumorigenic microenvironment through p21WAF1/CIP1 overexpression, which is reversed by metformin.

Prevention and treatment options for hepatocellular carcinoma (HCC) are presently limited, underscoring the necessity for further elucidating molecular mechanisms underlying HCC development and identifying new prevention and therapeutic targets. Here, we demonstrate a unique protumorigenic niche in the livers of Ncoa5+/- mouse model of HCC, which is characterized by altered expression of a subset of genes including p21WAF1/CIP1 and proinflammatory cytokine genes, increased putative hepatic progenitors, and expansions of activated and tissue-resident memory (TRM) CD8+ T lymphocytes, myeloid-derived suppressor cells (MDSCs), and alternatively activated M2 macrophages. Importantly, prophylactic metformin treatment reversed these characteristics including aberrant p21WAF1/CIP1 expression and subsequently reduced HCC incidence in Ncoa5+/- male mice. Heterozygous deletion of the p21WAF1/CIP1 gene alleviated the key features associated with the protumorigenic niche in the livers of Ncoa5+/- male mice. Moreover, transcriptomic analysis reveals that preneoplastic livers of Ncoa5+/- mice are similar to the livers of nonalcoholic steatohepatitis patients as well as the adjacent noncancerous liver tissues of a subset of HCC patients with a relatively poor prognosis. Together, our results suggest that p21WAF1/CIP1 overexpression is essential in the development of protumorigenic microenvironment induced by NCOA5 deficiency and metformin prevents HCC development via alleviating p21WAF1/CIP1 overexpression and protumorigenic microenvironment.

Positive feedback loop of FAM83A/PI3K/AKT/c-Jun induces migration, invasion and metastasis in hepatocellular carcinoma.

FAM83A is part of an 8-member protein family of unknown function and is reported to be a cancer-promoting and treatment-resistance factor in several cancers. However, its role in hepatocellular carcinoma (HCC) remains unclear. Analysis of the Cancer Genome Atlas (TCGA) showed that FAM83A mRNA expression is upregulated in HCC, as are the protein expression levels in both HCC cell lines and tissues. Clinical data have demonstrated that high FAM83A expression is positively correlated with poor progression-free survival time, thus suggesting its cancer-promoting potential. Functional analyses showed that FAM83A overexpression promoted HCC cell migration and invasion in vitro and suppressed sorafenib sensitivity. Inhibiting FAM83A reversed these results. A pulmonary metastasis model further confirmed that FAM83A promoted HCC cell metastasis in vivo. Mechanistic analyses indicated that FAM83A activated the PI3K/AKT signaling pathway, its downstream c-JUN protein, and epithelial-to-mesenchymal transition (EMT)-related protein levels, including downregulation of E-cadherin and upregulation of Vimentin and N-cadherin. Interestingly, c-JUN induced FAM83A expression by directly binding to its promoter region and thus forming a positive-feedback loop for FAM83A/PI3K/AKT/c-JUN. In conclusion, we demonstrated that FAM83A, as a cancer-metastasis promoter, accelerates migration, invasion and metastasis by activating the PI3K/AKT/c-JUN pathway and inducing its self-expression via feedback, thus forming a FAM83A/PI3K/AKT/c-JUN positive-feedback loop to activate EMT signaling and finally promote HCC migration, invasion and metastasis.

CD19 and CD30 CAR T-Cell Immunotherapy for High-Risk Classical Hodgkin's Lymphoma.

BACKGROUND: In clinical applications of CAR T-cell therapy, life-threatening adverse events including cytokine release syndrome and neurotoxicity can lead to treatment failure. Outcomes of patients treated with anti-CD30 CAR T- cell have been disappointing in relapsing/refractory (r/r) classical Hodgkin's Lymphoma (cHL). METHODS: In order to understand the applicable population of multiple CAR T-cell therapy, we examined the expression of CD19, CD20, and CD30 by immunohistochemistry (IHC) in 38 paraffin-embedded specimens of cHL. In the past two years, we found only one patient with cHL who is eligible for combined anti-CD19 and CD30 CAR T-cell treatment. This patient's baseline characteristics were prone to severe adverse events. We treated this patient with low doses and multiple infusions of anti-CD19 and CD30 CAR T-cell. RESULTS: The positive expression of CD19+ + CD30+ in Reed-Sternberg (RS) cells is approximately 5.2% (2/38). The patient we treated with combined anti-CD19 and CD30 CAR T-cell did not experience severe adverse events related to CAR T-cell therapy and received long term progression-free survival (PFS). CONCLUSION: For high risk r/r cHL patients, low doses of CAR T-cell used over different days at different times might be safe and effective. More clinical trials are warranted for CD19 and CD30 CAR T-cell combination therapy.

HBX-induced miR-5188 impairs FOXO1 to stimulate ß-catenin nuclear translocation and promotes tumor stemness in hepatocellular carcinoma.

Cancer stem cells (CSCs) are the key factor in determining cancer recurrence, metastasis, chemoresistance and patient prognosis in hepatocellular carcinoma (HCC). The role of miR-5188 in cancer stemness has never been documented. In this study, we investigated the clinical and biological roles of miR-5188 in HCC. Methods: MiRNA expression in HCC was analyzed by bioinformatics analysis and in situ hybridization. The biological effect of miR-5188 was demonstrated in both in vitro and in vivo studies through the ectopic expression of miR-5188. The target gene and molecular pathway of miR-5188 were characterized using bioinformatics tools, dual-luciferase reporter assays, gene knockdown, and rescue experiments. Results: MiR-5188 was shown to be upregulated and confer poor prognosis in HCC patient data from TCGA database. MiR-5188 was subsequently identified as a significant inducer of cancer stemness that promotes HCC pathogenesis. Specifically, the targeting of miR-5188 by its antagomir markedly prolonged the survival time of HCC-bearing mice and improved HCC cell chemosensitivity in vivo. Mechanistic analysis indicated that miR-5188 directly targets FOXO1, which interacts with ß-catenin in the cytoplasm to reduce the nuclear translocation of ß-catenin and promotes the activation of Wnt signaling and downstream tumor stemness, EMT, and c-Jun. Moreover, c-Jun transcriptionally activates miR-5188 expression, forming a positive feedback loop. Interestingly, the miR-5188-FOXO1/ß-catenin-c-Jun feedback loop was induced by hepatitis X protein (HBX) through Wnt signaling and participated in the HBX-induced pathogenesis of HCC. Finally, analyses of transcriptomics data and our clinical data supported the significance of the abnormal expression of the miR-5188 pathway in HCC pathogenesis. Conclusions: These findings present the inhibition of miR-5188 as a novel strategy for the efficient elimination of CSCs to prevent tumor metastasis, recurrence and chemoresistance in patients with hepatocellular carcinoma. Our study highlights the importance of miR-5188 as a tumor stemness inducer that acts as a potential target for HCC treatment.

HDGF and PRKCA upregulation is associated with a poor prognosis in patients with lung adenocarcinoma.

Lung adenocarcinoma is the most common histologic subtype of lung cancer. The aim of the present study was to assess the expression of hepatoma-derived growth factor (HDGF) and protein kinase Cα (PRKCA) in lung adenocarcinoma (LADC), and to determine the association between the combined expression of these two proteins and clinicopathological characteristics of patients with LADC. The expression of HDGF and PRKCA mRNA was assessed by GEO database analysis, and HDGF and PRKCA protein levels were examined by immunohistochemistry using a tissue microarray. High HDGF and PRKCA expression was observed in LADC tissue compared to normal samples, and increased HDGF and PRKCA expression was associated with AJCC clinical stage, tumor classification, node classification, and lymph node metastasis. GEO database analysis revealed no significant differences between HDGF mRNA and PRKCA mRNA in LADC tissue. However, high PRKCA protein expression was associated with high HDGF protein expression, and patients with high HDGF and PRKCA expression exhibited poorer overall survival rates than patients with low expression levels of the two proteins. The results of the present study suggest that upregulation of both HDGF and PRKCA may be an unfavourable factor for lung adenocarcinoma progression.

A cis-eQTL genetic variant in PLK4 confers high risk of hepatocellular carcinoma.

PURPOSE: The overexpression and knockdown of PLK4 were both reported to generate aneuploidy. Thus, we aimed to investigate whether genetic variants in PLK4 contribute to the development of hepatocellular carcinoma (HCC). METHODS: We evaluated associations of common variants in PLK4 and its promoter for the risk of HCC in our association study (1300 cases and 1344 controls). The genotype-tissue expression (GTEx) and The cancer genome atlas (TCGA) databases were used to quantify the expression of PLK4. Cell proliferation and migration affected by PLK4 in HCC were assessed in vitro. Drug susceptibility testing (DST) model was used to assess the sensibility of PLK4-activated HCC to CFI-400945, a small molecule inhibitor of PLK4. RESULTS: Herein, we found a significant association between rs3811741, located in the PLK4 intron, and liver cancer risk (OR = 1.26, P = 9.81 × 10-5 ). Although PLK4 expressed at lower levels in somatic tissues compared to the testis, the risk allele A of rs3811741 was associated with increased PLK4 expression in liver cancer tissues. Additionally, PLK4 high expression was remarkably associated with shortened survival of HCC (HR = 1.97, P = .001). Furthermore, overexpression of PLK4 promoted, while knockdown of PLK4 suppressed cancer cell proliferation, migration, and invasion. DST model demonstrated that CFI-400945 can effectively suppress rampant proliferation of HCC with highly expressed PLK4. CONCLUSION: Taken together, our study demonstrated that PLK4 is a susceptibility gene and plays an oncogenic role in HCC. Furthermore, we identified that PLK4 sensitives HCC to CFI-400945, which may be an ideal therapy target for HCC.

Curcumin inhibits cell proliferation and migration in NSCLC through a synergistic effect on the TLR4/MyD88 and EGFR pathways.

Despite the increasing number of available therapeutic methods, the prognosis of non­small cell lung cancer (NSCLC) remains poor. Furthermore, side effects are an important limiting factor in the treatment of NSCLC. Therefore, developing an efficacious, safe, affordable and easily accessible chemotherapeutic agent is necessary for NSCLC treatment. As a natural chemical produced by Zingiberaceae plants, curcumin exerts distinct antitumor effects on several tumor types. In the present study, curcumin was observed to inhibit not only cell proliferation and cell cycle transition, but also cell migration in NSCLC, as determined by a series of experiments (such as MTS assay, colony formation assay, flow cytometric analysis, Transwell migration assay and western blotting). Mechanistically, curcumin induced G2/M phase arrest by controlling cell cycle­ and epithelial­mesenchymal transition (EMT)­related checkpoints. Furthermore, curcumin significantly inhibited the expression of Toll­like receptor 4 (TLR4)/MyD88 and EGFR in a dose­ and time­dependent manner. Conversely, EGF reversed the inhibitory action of curcumin on TLR4/MyD88. In clinical specimens, TLR4 and MyD88 were highly expressed in NSCLC tissues, and a significant positive association was observed between TLR4 and MyD88 expression. These data suggested that curcumin may control the EGFR and TLR4/MyD88 pathways to synergistically downregulate downstream cell cycle­ and EMT­related regulators, in order to block cell proliferation and metastasis in NSCLC. These findings provide evidence for the clinical application of curcumin.

Blocking the PD-1/PD-L1 axis in dendritic cell-stimulated Cytokine-Induced Killer Cells with pembrolizumab enhances their therapeutic effects against hepatocellular carcinoma.

Immune checkpoint therapies for cancer, like the anti-programmed cell death 1 (PD-1) agent pembrolizumab, have gained considerable attention. However, the use of immune checkpoint inhibitors in the context of adoptive immunotherapy is poorly characterized. We investigated the therapeutic efficacy of dendritic cell-stimulated CIK (DC-CIK) cells pretreated with pembrolizumab against hepatocellular carcinoma (HCC) in cytotoxicity assay in vitro and in a nude mouse xenograft model. We used time-lapse imaging to investigate tumor killing. We also performed a survival analysis based on lymphocyte subpopulation-specific mRNA signatures using The Cancer Genome Atlas (TCGA) HCC cohort (n=371 patients). The results indicated that PD-1 inhibition increased the anti-tumor effects of DC-CIK cells over those of DC-CIK cells alone, resulting in a survival benefit importantly. Time-lapse imaging revealed that DC-CIK cells appeared to be more effective and aggressive after anti-PD-1 treatment than after culture in control conditions. The PD-1 inhibitor also induced more effective immune cell infiltration of the tumor. Our analysis of the TCGA HCC cohort confirmed that a genetic signature consistent with a high degree of intratumoral CD8+ T cell infiltration is associated with good prognosis. These results suggest that blockade of the PD-1/PD-L1 axis in DC-CIK cells with a PD-1 inhibitor prior to infusion is a promising therapeutic strategy against HCC.