Association of CTACK, IL-2, and IL-13 with increased risk of lung cancer: A Mendelian randomization study.

BACKGROUND: In recent years, relevant studies have reported that inflammatory cytokines are related to the occurrence of cancer. However, the correlation with lung cancer is not clear. This study used the Mendelian random grouping method to investigate the correlation between inflammatory factors and lung cancer in different populations. METHODS: We obtained the single nucleotide polymorphisms (SNPs) of inflammatory cytokines through the open database and the SNPs of lung cancer (European and East Asian) through the IEU OpenGWAS project. Inverse variance-weighted (IVW) MR analyses were used to determine the causalities of exposures and outcomes. Supplementary analyses were also performed using weighted median and MR-Egger regressions. Afterward, sensitivity analyses were performed to test the robustness. Search the ChEMBL database for target drugs and indications for CTACK, IL-2, and IL-13. RESULTS: By IVW method, we found that CTACK, IL-2, and IL-13 were associated with an increased risk of lung cancer in the European population (CTACK, OR = 1.098, 95 % CI 1.001-1.204, P = 0.047; IL-2, OR = 1.112, 95 % CI 1.009-1.225, P = 0.032; IL-13, OR = 1.068, 95 % CI 1.007-1.132, P = 0.029), while only IL-13 was associated with an increased risk of lung cancer in the East Asian population (IL-13, OR = 1.110, 95 % CI 1.010-1.220, P = 0.030). The weighted median and MR-Egger regression methods were in the same direction as the IVW effect sizes. Furthermore, no evidence of multidirectionality was detected using the MR-Egger intercept as a sensitivity analysis. Currently, there are no approved or phase III studied indications for CTACK, IL-2, and IL-13 targets in lung cancer. CONCLUSION: The study outcomes supported that the inflammatory cytokines CTACK, IL-2, and IL-13 increase the risk of lung cancer. There is a lack of indications for drugs in these three targets. We explored the causal relationship between inflammatory cytokines and lung cancer, providing a basis for future cancer prediction models and targets for anti-tumor therapy.

Tumor cell-induced platelet aggregation accelerates hematogenous metastasis of malignant melanoma by triggering macrophage recruitment.

BACKGROUND: Tumor cell-induced platelet aggregation (TCIPA) is not only a recognized mechanism for paraneoplastic thrombocytosis but also a potential breakthrough alternative for a low response to immune checkpoint inhibitors (ICIs) in hematogenous metastasis of malignant melanoma (MM). However, there is no TCIPA-specific model for further investigation of the relationship among TCIPA, the tumor immune microenvironment (TIME), and metastasis. METHODS: We developed a TCIPA metastatic melanoma model with advanced hematogenous metastasis and enhanced TCIPA characteristics. We also investigated the pathway for TCIPA in the TIME. RESULTS: We found that TCIPA triggers the recruitment of tumor-associated macrophages (TAMs) to lung metastases by secreting B16 cell-educated platelet-derived chemokines such as CCL2, SDF-1, and IL-1ß. Larger quantities of TAMs in the TCIPA model were polarized to the M2 type by B16 cell reprocessing, and their surface programmed cell death 1 ligand 1 (PD-L1) expression was upregulated, ultimately assisting B16 cells in escaping host immunity and accelerating MM hematogenous metastasis. CONCLUSIONS: TCIPA accelerates MM lung metastasis via tumor-educated platelets (TEPs), triggering TAM recruitment, promoting TAM polarization (M2), and remodeling the suppressive TIME in lung metastases.

IPSC-derived CAR-NK cells for cancer immunotherapy.

Adoptive cell therapies (ACT) based on chimeric antigen receptor (CAR)-modified immune cells have made great progress with six CAR-T cell products approved by the U.S. FDA for hematological malignancies. Compared with CAR-T cells, CAR-NK cells have attracted increasing attention owing to their multiple killing mechanisms, higher safety profile, and broad sources. Induced pluripotent stem cell (iPSC)-derived NK (iPSC-NK) cells possess a mature phenotype and potent cytolytic activity, and can provide a homogeneous population of CAR-NK cells that can be expanded to clinical scale. Thus, iPSC-derived CAR-NK (CAR-iNK) cells could be used as a standardized and "off-the-shelf" product for cancer immunotherapy. In this review, we summarize the current status of the manufacturing techniques, genetic modification strategies, preclinical and clinical evidence of CAR-iNK cells, and discuss the challenges and future prospects of CAR-iNK cell therapy as a novel cellular immunotherapy in cancer.

Overexpression of POU3F2 promotes radioresistance in triple-negative breast cancer via Akt pathway activation.

PURPOSE: POU3F2 is associated with malignant behaviors and poor prognosis in cancer. However, the function and mechanism of POU3F2 in breast cancer remain to be elucidated. Our study aimed to explore the role of POU3F2 in triple-negative breast cancer and radiotherapy. METHODS: POU3F2 expression was examined by RT-PCR and Western blot. The proliferation of cancer cells was measured by MTT assay. Migration of cancer cells was determined by Transwell assay and wound healing assay. To determine which protein interacts with POU3F2, Co-IP was performed. Survival analysis was performed based on the online database GEPIA. DNA damage after radiation was examined by Comet Assay. Radiosensitivity was evaluated with clonogenic survival assays. A tumor xenograft model was established with MDA-MB-231 breast cancer cells in BALB/c nude mice to explore the effect of POU3F2 in vivo. RESULTS: We found that the expression of POU3F2 was significantly elevated in breast cancer cells, especially in TNBC, and higher POU3F2 expression was related to poor prognosis of patients with breast cancer. Functional assays revealed that POU3F2 promoted proliferation, migration, and invasion of triple-negative breast cancer (TNBC) cells in vitro and in vivo. In addition, the knockdown of POU3F2 decreased the radioresistance of TNBC cells in vitro. Furthermore, POU3F2 could enhance the activation of the Akt pathway by interacting with ARNT2, thereby promoting proliferation and radioresistance in TNBC cells. CONCLUSIONS: Our results provide evidence that high expression of POU3F2 promotes radioresistance in triple-negative breast cancer via Akt pathway activation by interacting with ARNT2.

Effects of traditional Chinese medicine combined with chemotherapy for extensive-stage small-cell lung cancer patients on improving oncologic survival: study protocol of a multicenter, randomized, single-blind, placebo-controlled trial.

BACKGROUND: Extensive-stage small-cell lung cancer (ES-SCLC) is characterized by extensive metastases, aggressive progression, and poor prognosis. Chemotherapy is applied as a preferred first-line regimen for ES-SCLC, but inadequate for improving its overall survival. Traditional Chinese medicine (TCM) is widely used in the clinical practice of ES-SCLC for its synergy with chemotherapy. However, there is still no substantial evidence to prove that TCM can effectively improve the long-term efficacy of ES-SCLC patients. The study intends to determine whether the TCM with chemotherapy can improve the overall survival (OS) in treating with ES-SCLC when compared with chemotherapy alone. METHOD/DESIGN: A multicenter, randomized, single-blind, placebo-controlled clinical trial will be conducted to determine whether the TCM granules combined with chemotherapy can improve the OS of ES-SCLC. Two hundred seventy participants will randomly receive 4-6 cycles (21 days per cycle) of chemotherapy plus TCM granules or placebo. The primary outcome measure is OS. The secondary outcome measures includes progression-free survival (PFS), objective response rate (ORR), quality of life (QoL), and tumor markers. Visits will be performed at the end of each cycle during the treatment period and then every 3 months in the follow-up period until the patients' death or study completion. DISCUSSION: The study's result will provide a high-level evidence for TCM granules using with chemotherapy on the first-line treatment of ES-SCLC. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1900022991 . Registered on 6 May 2019 (prospective registration).

A network-based predictive gene expression signature for recurrence risks in stage II colorectal cancer.

The current criteria for defining the recurrence risks of stage II colorectal cancer (CRC) are not robust; therefore, we aimed to explore novel gene signatures to predict recurrence risks and to reveal the underlying mechanisms of stage II CRC. First, the gene expression profiles of 124 patients with stage II CRC from The Cancer Genome Atlas (TCGA) database were obtained to screen differentially expressed genes (DEGs). A total of 202 DEGs, including 128 upregulated and 74 downregulated, were identified in the recurrence group (n = 24) compared to the nonrecurrence group (n = 100). Furthermore, the top 5 DEGs (ZNF561, WFS1, SLC2A1, MFI2, and PTGR1) were identified by random forest variable hunting, and four (ZNF561, WFS1, SLC2A1, and PTGR1) were selected to create a four-gene recurrent model (GRM), with an area under the curve (AUC) of 0.882 according to the receiver operating characteristic curve, and the robust diagnostic effectiveness of the GRM was further validated with another gene expression profiling dataset (GSE12032), with an AUC of 0.943. The diagnostic effectiveness of the GRM regarding recurrence was associated with poor disease-free survival in all stages of CRC. In addition, gene ontology functional annotation and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses revealed 18 enriched functions and 6 enriched pathways. Four genes, ABCG2, CACNA1F, CYP19A1, and TF, were identified as hub genes by the protein-protein interaction network, which further validated that these genes were correlated with a poor pathologic stage and overall survival in all stages of CRC. In conclusion, the GRM can effectively classify stage II CRC into groups of high and low risks of recurrence, thereby making up for the prognostic value of the traditional clinicopathological risk factors defined by the National Comprehensive Cancer Network guidelines. The hub genes may be useful therapeutic targets for recurrence. Thus, the GRM and hub genes could offer clinical value in directing individualized and precision therapeutic regimens for stage II CRC patients.