"Find Me" and "Eat Me" signals: tools to drive phagocytic processes for modulating antitumor immunity.

Phagocytosis, a vital defense mechanism, involves the recognition and elimination of foreign substances by cells. Phagocytes, such as neutrophils and macrophages, rapidly respond to invaders; macrophages are especially important in later stages of the immune response. They detect "find me" signals to locate apoptotic cells and migrate toward them. Apoptotic cells then send "eat me" signals that are recognized by phagocytes via specific receptors. "Find me" and "eat me" signals can be strategically harnessed to modulate antitumor immunity in support of cancer therapy. These signals, such as calreticulin and phosphatidylserine, mediate potent pro-phagocytic effects, thereby promoting the engulfment of dying cells or their remnants by macrophages, neutrophils, and dendritic cells and inducing tumor cell death. This review summarizes the phagocytic "find me" and "eat me" signals, including their concepts, signaling mechanisms, involved ligands, and functions. Furthermore, we delineate the relationships between "find me" and "eat me" signaling molecules and tumors, especially the roles of these molecules in tumor initiation, progression, diagnosis, and patient prognosis. The interplay of these signals with tumor biology is elucidated, and specific approaches to modulate "find me" and "eat me" signals and enhance antitumor immunity are explored. Additionally, novel therapeutic strategies that combine "find me" and "eat me" signals to better bridge innate and adaptive immunity in the treatment of cancer patients are discussed.

Identification and immunological characterization of PLA2G2A and cell death-associated molecular clusters in idiopathic pulmonary fibrosis.

AIMS: Idiopathic pulmonary fibrosis (IPF) is a severe pulmonary interstitial pneumonia. Our study focuses on the role of PLA2 enzyme in the IPF to explore a more effective diagnosis and treatment mechanism of IPF. MAIN METHODS: Transcriptome data of IPF from GEO database and bleomycin-induced pulmonary fibrosis mice were analyzed to identify PLA2 enzyme and their metabolite, lysophosphatidylcholines 18:0, in IPF. Based on PLA2G2A and PLA2G2D / PLA2G2A-associated cell death genes (PCDs), the consensus clustering analysis was used to identify the subtypes of IPF and the correlation between PLA2G2A and prognosis was analyzed. The machine learning (ML) models and artificial neural network (ANN) model was used to validate the diagnostic accuracy of PLA2s and PCDs in diagnosing IPF. The gene and protein expression of NLRP3, GSDMD, and CASP-1 was estimated in recombinant PLA2G2A protein induced MLE-12 cells. KEY FINDINGS: The expression of PLA2G2D, PLA2G2A, and LPC18 significantly changed in IPF. Furtherly, PLA2G2A has a significant correlation with poor patient prognosis, which could predict the 2 or 3-years mortality rates of IPF. Two subtypes of IPF patients, identified based on PCDs, showed significant different immunoinfiltration. Recombinant PLA2G2A protein could induce the pyrotosis in the MLE-12 cell. The generalized linear model and ANN model of PLA2s or PCDs accurate diagnosis IPF. SIGNIFICANCE: PLA2G2A is the most robustly associated gene with IPF among the PLA2s, which demonstrates a potential in diagnosing and prognostic value in IPF, and provides a foundation for further understanding and breakthroughs in IPF diagnosis and treatment.

Development and validation of immunogenic cell death-applied prediction model for esophageal carcinoma.

Evidence suggests that immunogenic cell death (ICD) releases cancer antigens that promote cytotoxic T-cell responses, potentially improving immunotherapy. However, the relationship between ICDs and esophageal cancer (EC) remains unclear. This study aimed to determine the role of ICDs in EC and to construct an ICD-based prognostic panel. RNA-seq data of EC and the corresponding clinical information were downloaded from the UCSC-Xena platform to explore the association between ICD gene expression and EC prognosis. The GSE53625 dataset was used to validate the proposed model. Differentially expressed genes (DEGs) between different molecular subtypes were identified to construct a new ICD-related prognosis panel and generate molecular subtypes using ConsensusClusterPlus. We created a prognostic profile based on the ICD and a nomogram based on the risk score. Compared with normal samples, ICD gene expression of malignant samples were significantly increased. 161 patients with EC were successfully divided into three subtypes (SubA, SubB, and SubC). Patients with EC in the SubC group had the best survival and lowest ICD score, whereas patients in the SubB group had the worst prognosis. DEGs between subtypes were evaluated, and risk panels were established using LASSO-Cox regression analysis. The prognosis of low-risk patients was significantly better than that of high-risk patients in both cohorts. The area under the curve of the receiver operating characteristic curve indicated that the risk group had a good prognostic value. Our study identified the molecular subtypes of EC and ICD-based prognostic signatures. Our three-gene risk panel could serve as a biomarker for effectively assessing the prognostic risk of patients with EC.

Comprehensive profiling of EGFR mutation subtypes reveals genomic-clinical associations in non-small-cell lung cancer patients on first-generation EGFR inhibitors.

Common sensitizing mutations in epidermal growth factor receptor (cEGFR), including exon 19 deletions (19-Del) and exon 21 L858R substitution, are associated with high sensitivity to EGFR-TKIs in NSCLC patients. The treatment for NSCLC patients with uncommon EGFR (uEGFR) mutations remains a subject of debate due to heterogeneity in treatment responses. In this manuscript, the targeted next-generation sequencing (NGS) data of a large cohort of EGFR-mutated NSCLC patients was assessed to elucidate genomic profiles of tumors carrying cEGFR or uEGFR mutations. The results showed that NSCLC patients with uEGFR mutations were more likely to harbor co-occurring genetic alterations in the Hippo pathway and a higher TMB compared with cEGFR-positive patients. Smoking-related mutations were found to significantly enriched in uEGFR-positive patients. Subgroup analyses were performed to identify potential prognostic biomarkers in patients harboring various EGFR subtype mutations. L858R-positive patients with co-existing ARID2 mutations had shorter progression-free survival (PFS) than those who were L858R- or 19-Del-positive but ARID2-negative (median: 2.3 vs. 12.0 vs. 8.0 months, P = 0.038). Furthermore, mutational profiles, such as top frequently mutated genes and mutational signatures of patients with various EGFR subtype mutations were significantly different. Our study analyzed the mutational landscape of NSCLC patients harboring cEGFR and uEGFR mutations, revealing specific genomic characteristics associated with uEGFR mutations that might explain the poor prognosis of first-generation EGFR-TKIs.

Engineering c-Met-CAR NK-92 cells as a promising therapeutic candidate for lung adenocarcinoma.

Mesenchymal-epithelial transition factor (C-Met) has been acknowledged as a significant therapeutic target for treating lung adenocarcinoma (LUAD). However, the potential application of chimeric antigen receptors (CAR)-modified natural killer (NK) cells targeting c-Met in LUAD is rarely explored. In this study, bioinformatic databases were searched and a tissue microarray (TMA) was enrolled to investigate expression status and prognostic role of c-Met in LUAD. Then, four types of c-Met-CAR structures were designed and prepared. The engineering CAR-NK cells containing c-Met-CARs were transfected, verified and characterized. The tumor-inhibitory role of c-Met-CAR-NK cells was finally evaluated in vitro and in vivo. The results demonstrated that c-Met expression elevated and confirmed that high c-Met expression was significantly associated with unfavorable prognosis in LUAD. Then, C-Met-CAR-NK cells were successfully constructed and DAP10 designed in CAR structure was a favorable stimulator for NK cell activation. CCN4 containing DAP10 co-stimulator exhibited the strongest cytotoxicity compared with other CAR-NK cells. Furthermore, CCN4 cells also exerted the prominent tumor-inhibitory effect on xenograft tumor growth. Collectively, this study suggests that DAP10 is a potent stimulator in CAR structure for NK cell activation, and CCN4-based immunotherapy may represent a promising strategy for the treatment of c-Met-positive LUAD.

A novel immune checkpoint siglec-15 antibody inhibits LUAD by modulating mφ polarization in TME.

BACKGROUND: Siglec-15 (S15) is a type-I transmembrane protein and is considered a new candidate of immune checkpoint inhibitor for cancer immunotherapy. METHODS: In the present study, we first constructed and characterized a chimeric S15-specific monoclonal antibody (S15-4E6A). Then, the antitumor effectiveness and modulatory role of S15-4E6A in macrophages (mφs) were explored in vitro and in vivo. Finally, the underlying mechanism by which S15mAb inhibits LUAD was preliminarily explored. RESULTS: The results demonstrated the successful construction of S15-4E6A, and S15-4E6A exerted an efficacious tumor-inhibitory effect on LUAD cells and xenografts. S15-4E6A could promote M1-mφ polarization while inhibiting M2-mφ polarization, both in vitro and in vivo. CONCLUSIONS: S15-based immunotherapy that functions by modulating mφ polarization may be a promising strategy for the treatment of S15-positive LUAD.

Non-intubated uniportal subxiphoid thoracoscopic extended thymectomy for thymoma associated with myasthenia gravis.

BACKGROUND: To describe a technique of non-intubated uniportal subxiphoid thoracoscopic extended thymectomy. METHODS: Data were collected retrospectively. A single 3-cm transverse incision was made below the xiphoid process. This method for extended thymectomy entails adoption of uniportal subxiphoid VATS combined with using of non-intubated anesthesia for thymoma associated with myasthenia gravis. RESULTS: Ten consecutive patients underwent this procedure successfully. Mean operative time was 102.5 min. Conversion to intubated ventilation or thoracotomy was not required. Mean chest tube duration was 3.5 days. Mean postoperative hospital stay was 4.7 days. Histologic examination showed early-stage thymomas. Side effects were rare. Quantitative MG scores decreased during follow-up. CONCLUSIONS: Patients were uneventfully discharged with fast recovery. This technique may merge the potential benefits of a subxiphoid incision and the non-intubated anesthesia protocol.

MAGE-A1 in lung adenocarcinoma as a promising target of chimeric antigen receptor T cells.

BACKGROUND: Cancer/testis antigens (CTAs) are a special type of tumor antigen and are believed to act as potential targets for cancer immunotherapy. METHODS: In this study, we first screened a rational CTA MAGE-A1 for lung adenocarcinoma (LUAD) and explored the detailed characteristics of MAGE-A1 in LUAD development through a series of phenotypic experiments. Then, we developed a novel MAGE-A1-CAR-T cell (mCART) using lentiviral vector based on our previous MAGE-A1-scFv. The anti-tumor effects of this mCART were finally investigated in vitro and in vivo. RESULTS: The results showed striking malignant behaviors of MAGE-A1 in LUAD development, which further validated the rationality of MAGE-A1 as an appropriate target for LUAD treatment. Then, the innovative mCART was successfully constructed, and mCART displayed encouraging tumor-inhibitory efficacy in LUAD cells and xenografts. CONCLUSIONS: Taken together, our data suggest that MAGE-A1 is a promising candidate marker for LUAD therapy and the MAGE-A1-specific CAR-T cell immunotherapy may be an effective strategy for the treatment of MAGE-A1-positive LUAD.

FLOT1 promotes tumor development, induces epithelial-mesenchymal transition, and modulates the cell cycle by regulating the Erk/Akt signaling pathway in lung adenocarcinoma.

BACKGROUND: FLOT1 is a scaffolding protein of lipid rafts that is believed to be involved in numerous cellular processes. However, few studies have explored the function of FLOT1 in the development of lung adenocarcinoma (LUAD) and the underlying mechanisms of FLOT1 activity. METHODS: FLOT1 knockdown and overexpression models were constructed via lentivirus. Cell growth, invasion, migration, and apoptosis were detected to evaluate the role of FLOT1 in LUAD development. Epithelial-mesenchymal transition (EMT) and cell cycle regulatory markers were then examined. Finally, the influence of FLOT1 on the Erk/Akt signaling pathway was investigated. RESULTS: FLOT1 promoted cell growth, invasion, and migration and inhibited cell apoptosis. In addition, FLOT1 induced EMT and modulated the cell cycle by activating the Erk/Akt signaling pathway. CONCLUSION: The findings indicate a significant role of FLOT1 in LUAD development. Targeting FLOT1 may be a potential therapeutic strategy for LUAD.

ROR1 associates unfavorable prognosis and promotes lymphoma growth in DLBCL by affecting PI3K/Akt/mTOR signaling pathway.

The receptor-tyrosine-kinase (RTK)-like orphan receptor 1 (ROR1) is a transmembrane glycoprotein regarded as a tumor-associated antigen. ROR1 plays an important role in cancer development, but the detailed function of ROR1 in diffuse large B-cell lymphoma (DLBCL) remains unclear. In this study, we first detected ROR1 expression and evaluated the relationship between ROR1 expression and the clinicopathological characteristics of DLBCL patients. Next we employed shRNA-mediated knockdown of ROR1 in DLBCL cell line to explore the characteristics of ROR1 in DLBCL development both in vitro and in vivo. The results showed a significantly higher level of ROR1 in DLBCL tissues than in lymphatic hyperplasia tissues. High ROR1 expression was correlated with unfavorable prognosis in DLBCL patients. Furthermore, ROR1 knockdown inhibited the growth and induced the apoptosis in DLBCL cells and xenografts. In addition, shROR1 inhibited activation of the PI3K/Akt/mTOR signaling pathway, both in vitro and in vivo. Taken together, our results suggest that ROR1 is a novel prognostic marker for DLBCL survival and ROR1 significantly promotes DLBCL tumorigenesis by regulating the PI3K/Akt/mTOR signaling pathway. Targeting ROR1 may provide a promising strategy for DLBCL treatment. © 2019 BioFactors, 45(3):416-426, 2019.

Subxiphoid versus lateral intercostal approaches thoracoscopic thymectomy for non-myasthenic early-stage thymoma: A propensity score -matched analysis.

BACKGROUND: Thymectomy is increasingly being performed via minimally invasive approaches. The present study aimed to assess the safety and feasibility of the subxiphoid approach to video-assisted thoracic surgery (VATS) compared with the lateral intercostal approach VATS. METHODS: Patients who underwent VATS thymectomy via subxiphoid and lateral intercostal approaches in our hospital between 2015 and 2018 were retrospectively analyzed. A series of perioperative outcomes, including clinical and surgical results, postoperative pain scores and cosmetic results, was compared in a propensity score matching analysis. RESULTS: A total of 98 patients diagnosed with non-myasthenic early-stage thymoma underwent complete thymectomy by VATS. Propensity score analysis revealed that 28 patients treated with the subxiphoid approach and 28 patients treated with the lateral intercostal approach had the same baseline characteristics. Compared with those in the lateral intercostal approach group, patients in the subxiphoidapproach group yielded lower pain scores and shorter postoperative hospital stays. Other advantages of the subxiphoid approach included decreased inflammatory cytokine response and superior cosmesis. There were no significant differences in postoperative complications between the two groups. All these patients recovered well when discharged. There were no perioperative deaths. CONCLUSIONS: Our data suggest that subxiphoid and subcostal arch thoracoscopic radical thymectomy is a less invasive procedure for the treatment of non-myasthenic early-stage thymoma and provides a satisfactory cosmetic effect. Owing to the limitation ofour retrospective study, further prospective studies are needed to evaluate long-term and oncologic outcomes of subxiphoid approach VATS thymectomy.

A network-based signature to predict the survival of non-smoking lung adenocarcinoma.

BACKGROUND: A substantial increase in the number of non-smoking lung adenocarcinoma (LAC) patients has been drawing extensive attention in the past decade. However, effective biomarkers, which could guide the precise treatment, are still limited for identifying high-risk patients. Here, we provide a network-based signature to predict the survival of non-smoking LAC. MATERIALS AND METHODS: Gene expression profiles were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus. Significant gene co-expression networks and hub genes were identified by Weighted Gene Co-expression Network Analysis. Potential mechanisms and pathways of co-expression networks were analyzed by Gene Ontology. The predictive signature was constructed by penalized Cox regression analysis and tested in two independent datasets. RESULTS: Two distinct co-expression modules were significantly correlated with the non-smoking status across 4 Gene Expression Omnibus datasets. Gene Ontology revealed that nuclear division and cell cycle pathways were main mechanisms of the blue module and that genes in the turquoise module were involved in lymphocyte activation and cell adhesion pathways. Seventeen genes were selected from hub genes at an optimal lambda value and built the prognostic signature. The prognostic signature distinguished the survival of non-smoking LAC (training: hazard ratio [HR]=3.696, 95% CI: 2.025-6.748, P<0.001; testing: HR=2.9, 95% CI: 1.322-6.789, P=0.006; HR=2.78, 95% CI: 1.658-6.654, P=0.022) and had moderate predictive abilities in the training and validation datasets. CONCLUSION: The prognostic signature is a promising predictor of non-smoking LAC patients, which might benefit clinical practice and precision therapeutic management.

Rab27b Is a Potential Indicator for Lymph Node Metastasis and Unfavorable Prognosis in Lung Adenocarcinoma.

Rab27b is reported to associate with the development and progression of several types of human cancers. However, the relationship between Rab27b expression and the clinical characteristics of lung adenocarcinoma (LUAD) is rarely explored. In this present study, the TCGA database was consulted, followed by one-step quantitative reverse transcription polymerase chain reaction (qPCR), Western blot, and immunohistochemistry (IHC) analyses in LUAD cell lines and tissue samples. Rab27b expression levels were statistically higher in LUAD cell lines and tissue samples compared with a noncancerous cell line and tissue samples (p < 0.05). Rab27b expression was statistically correlated with lymph node metastasis (p = 0.016) and TNM stage (p = 0.019). Survival analysis and Kaplan-Meier curve revealed that Rab27b expression (p = 0.006) and TNM stage (p = 0.027) were independently associated with the unfavorable overall survival of patients with LUAD. These results indicate that high expression of Rab27b correlates with malignant attributes of LUAD and Rab27b may be identified as a potential indicator of metastasis and prognosis for LUAD.

Comparison of the oncologic outcomes of anatomic segmentectomy and lobectomy for early-stage non-small cell lung cancer.

Interest has been renewed in segmentectomy for non-small cell lung cancer (NSCLC). However, whether the oncologic outcomes are comparable with lobectomy is conflicting. To assess the evidence base, a systematic search identified 31 comparative studies for meta-analysis. No higher local or distant recurrence in segmentectomy compared with lobectomy. Nevertheless, worse outcomes in overall and recurrence-free survival for patients treated with segmentectomy were found. Lobectomy conferred a significant survival advantage compared with segmentectomy for stage I. However, segmentectomy was more suitable for stage IA NSCLC, with survivals equivalent to lobectomy. Further randomized controlled trials are needed to confirm the results.

MicroRNA-143 inhibits tumor growth and angiogenesis and sensitizes chemosensitivity to oxaliplatin in colorectal cancers.

Colorectal cancer (CRC) is one of the leading cancer-related causes of death in the world. Recently, downregulation of microRNA-143 (miR-143) has been observed in CRC tissues. Here in this study, we found that miR-143 expression was downregulated both in CRC patients' blood samples and tumor specimens. MiR-143 expression levels were strongly correlated with clinical stages and lymph node metastasis. Furthermore, insulin-like growth factor-I receptor (IGF-IR), a known oncogene, was a novel direct target of miR-143, whose expression levels were inversely correlated with miR-143 expression in human CRC specimens. Overexpression of miR-143 inhibited cell proliferation, migration, tumor growth and angiogenesis and increased chemosensitivity to oxaliplatin treatment in an IGF-IR-dependent manner. Taken together, these results revealed that miR-143 levels in human blood and tumor tissues are associated with CRC cancer occurrence, metastasis and drug resistance, and miR-143 levels may be used as a new diagnostic marker and therapeutic target for CRC in the future.

Nucleotide excision repair gene ERCC1 polymorphisms contribute to cancer susceptibility: a meta-analysis.

Individual studies of the associations between excision repair cross-complimentary group 1 (ERCC1) polymorphisms and cancer susceptibility have shown inconclusive results. To derive a more precise estimation of the relationship between three well-characterised polymorphisms on ERCC1 and the risk of cancer, we performed a meta-analysis based on 48 publications. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the associations. We found that ERCC1 17677A (rs3212961) variant genotypes were associated with significantly increased overall risk of cancer without substantial heterogeneity (AA versus CC, OR = 1.36, 95% CIs: 1.10-1.68; AC versus CC: OR = 1.11, 95% CIs: 0.99-1.26; dominant comparison: AA/AC versus CC: OR = 1.15, 95% CIs: 1.02-1.29; recessive comparison: AA versus AC/CC: OR = 1.25, 95% CIs: 1.05-1.49). The ERCC1 19007 C (rs11615) allele had null effects on overall risk of cancer; but in the stratified analyses, we observed an elevated association in Asian populations with homozygote variants and hospital-based controls. In addition, during further stratified analyses of cancer groups, homozygote variants were found that are associated with lung cancer and smoking-related cancers. Also, the observed ERCC1 19007 C heterozygote variant contributes to the development of skin cancer. However, the ERCC1 8092C > A (rs3212986) polymorphism did not appear to have an effect on cancer risk. Additionally, no evidence of publication bias was observed in these polymorphisms. Our meta-analysis supports the conclusion that the ERCC1 17677A > C and ERCC1 19007T > C polymorphisms, but not the ERCC1 8092C > A polymorphism, are low-penetrance risk factors for cancer development.

Cyclin D1 G870A polymorphism and colorectal cancer susceptibility: a meta-analysis of 20 populations.

PURPOSE: Studies investigating the association between genetic polymorphism of cyclin D1 (CCND1) G870A and risk of colorectal cancer (CRC) reported conflicting results. In order to derive a more precise estimation of the relationship, a meta-analysis was performed. MATERIALS AND METHODS: We performed an extensive search of relevant studies and carried out a meta-analysis, including 20 studies with 5,975 cases and 8,333 controls, to obtain a more precise estimate. RESULTS: Overall, significantly elevated colorectal cancer risk was associated with variant allele 870A when all studies were pooled (AA vs. GG: OR = 1.23, 95% CI = 1.04-1.44; GA vs. GG: OR = 1.13, 95% CI = 1.01-1.26; dominant model: OR = 1.16, 95% CI = 1.03-1.31). In the subgroup analysis by ethnicity, significantly increased risks were detected among Caucasians (AA vs. GG: OR = 1.27, 95% CI = 1.04-1.44; dominant model: OR = 1.17, 95% CI = 1.02-1.34).We also observed sporadic CRC with an increased cancer susceptibility (AA vs. GG: OR = 1.24, 95% CI = 1.04-1.48; dominant model: OR = 1.17, 95% CI = 1.04-1.33), when colorectal cancer was stratified into sporadic CRC and hereditary nonpolyposis colorectal cancer (HNPCC). However, no significant associations were found in both Asians and HNPCC patients for all genetic models. CONCLUSION: Result suggests that the cyclin D1 870A allele is a low-penetrant risk factor for developing sporadic colorectal cancer, especially among Caucasians.