ILT4 facilitates angiogenesis in non-small cell lung cancer.

Antiangiogenic therapy targeting VEGF-A has become the standard of first-line therapy for non-small cell lung cancer (NSCLC). However, its clinical response rate is still less than 50%, and most patients eventually develop resistance, even when using combination therapy with chemotherapy. The major cause of resistance is the activation of complex bypass signals that induce angiogenesis and tumor progression. Therefore, exploring novel proangiogenic mechanisms and developing promising targets for combination therapy are crucial for improving the efficacy of antiangiogenic therapy. Immunoglobulin-like transcript (ILT) 4 is a classic immunosuppressive molecule that inhibits myeloid cell activation. Recent studies have shown that tumor cell-derived ILT4 drives tumor progression via the induction of malignant biologies and creation of an immunosuppressive microenvironment. However, whether and how ILT4 participates in NSCLC angiogenesis remain elusive. Herein, we found that enriched ILT4 in NSCLC is positively correlated with high microvessel density, advanced disease, and poor overall survival. Tumor cell-derived ILT4 induced angiogenesis both in vitro and in vivo and tumor progression and metastasis in vivo. Mechanistically, ILT4 was upregulated by its ligand angiopoietin-like protein 2 (ANGPTL2). Their interaction subsequently activated the ERK1/2 signaling pathway to increase the secretion of the proangiogenic factors VEGF-A and MMP-9, which are responsible for NSCLC angiogenesis. Our study explored a novel mechanism for ILT4-induced tumor progression and provided a potential target for antiangiogenic therapy in NSCLC.

Efficacy of first-line treatment options beyond RET-TKIs in advanced RET-rearranged non-small cell lung cancer: A multi-center real-world study.

BACKGROUND: Although RET-tyrosine kinase inhibitors (RET-TKIs) are the preferred first-line therapy for advanced RET-arranged NSCLC, most patients cannot afford them. In this population, bevacizumab, immunotherapy, and chemotherapy are the most commonly used regimens. However, the optimal scheme beyond RET-TKIs has not been defined in the first-line setting. METHODS: This retrospective study included 86 stage IV NSCLC patients harboring RET rearrangement from six cancer centers between May 2017 and October 2022. RET-TKIs, chemotherapy, or one of the combination therapies (including immune checkpoint inhibitor (ICI) combined with chemotherapy (I + C), bevacizumab combined with chemotherapy (B + C), ICI and bevacizumab combined with chemotherapy (I + B + C)), were used as the first-line therapeutics. The clinical outcomes and safety were evaluated. RESULTS: Fourteen of the 86 patients received RET-TKIs, 57 received combination therapies, and 15 received chemotherapy alone. Their medium PFS (mPFS) were 16.92 months (95% CI: 5.9-27.9 months), 8.7 months (95% CI: 6.5-11.0 months), and 5.55 months (95% CI: 2.4-8.7 months) respectively. Among all the combination schemes, B + C (p = 0.007) or I + B + C (p = 0.025) gave beneficial PFS compared with chemotherapy, while I + C treatment (p = 0.169) generated comparable PFS with chemotherapy. In addition, I + B + C treatment had a numerically longer mPFS (12.21 months) compared with B + C (8.74 months) or I + C (7.89 months) schemes. In terms of safety, I + B + C treatment led to the highest frequency of hematological toxicity (50%) and vomiting (75%), but no ≥G3 adverse effect was observed. CONCLUSIONS: I + B + C might be a preferred option beyond RET-TKIs in the first-line therapy of RET-arranged NSCLC. Combination with Bevacizumab rather than with ICIs offered favorable survival compared with chemotherapy alone.

Tumor-derived Immunoglobulin-like transcript 4 facilitates angiogenesis of colorectal cancer.

Current anti-angiogenic therapies have changed the paradigm of treating colorectal cancer (CRC) patients with advanced diseases. However, the clinical response rate is still low at less than 10% due largely to complex angiogenic factors released by tumor cells. Exploring novel mechanisms of tumor angiogenesis and identifying alternative targets for combination therapies are therefore essential to effective inhibition of tumor vascularization and CRC development. Immunoglobulin-like transcript 4 (ILT4), initially identified as a suppressor of myeloid cell activity, is enriched in solid tumor cells. ILT4 favors tumor progression by inducing tumor malignant biologies as well as an immunosuppressive microenvironment. However, whether and how tumor-derived ILT4 orchestrates tumor angiogenesis is still undetermined. Here we found that tumor-derived ILT4 was positively correlated with microvessel density in CRC tissues. ILT4 induced the migration and tube formation of HUVECs in vitro and angiogenesis in vivo. Mechanistically, the activation of MAPK/ERK signaling and subsequent up-regulation of vascular endothelial growth factor-A (VEGF-A) and fibroblast growth factor 1 (FGF-1) were responsible for ILT4-induced angiogenesis and tumor progression. Importantly, ILT4 inhibition suppressed tumor angiogenesis and enhanced the efficacy of Bevacizumab treatment in CRC. Our study has identified a novel mechanism for ILT4-mediated tumor progression, which signals a new therapeutic target and alternative combination strategies to combat CRC.

Value of pretreatment serum lactate dehydrogenase as a prognostic and predictive factor for small-cell lung cancer patients treated with first-line platinum-containing chemotherapy.

BACKGROUND: The current study aimed to evaluate the serum pretreatment lactate dehydrogenase (LDH) and overall survival (OS) in small cell lung cancer (SCLC) patients who received first-line platinum-containing chemotherapy. METHODS: A total of 234 SCLC patients, who received first-line platinum-based chemotherapy between 2013 and 2018, were retrospectively analyzed. The data of hematological characteristics, age, gender, ECOG score, staging, metastatic site, smoking history, chemotherapy cycle, thoracic radiotherapy and hyponatremia were collected. Overall survival was calculated using the Kaplan-Meier method. The statistically significant factors in the univariate analysis were selected for the multivariate COX model analysis. RESULTS: Age, ECOG score, stage, thoracic radiotherapy, hyponatremia, liver metastasis, brain metastasis, bone metastasis, LDH, NSE and neutrophil-to-lymphocyte ratio (NLR) were closely correlated to OS in the univariate analysis. Furthermore, the multivariate analysis revealed that age (<65 years), ECOG score (<2 points), limited-stage (LD), thoracic radiotherapy and LDH <215.70 U/L were the independent prognostic factors for survival. The median OS time was worse for patients with LDH ≥215.70 U/L. In the subgroup analysis, LDH ≥215.70 U/L was significant for survival in both limited and extensive disease. Patients who achieved CR + PR in the first-line treatment had lower initial LDH levels. It was found that the pretreatment LDH increased the incidence of patients with liver metastasis. CONCLUSIONS: Positive independent prognostic factors for SCLC patients were age < 65 years old, ECOG score < 2 points, LD-SCLC, and pretreatment LDH <215.70 U/L. These factors may be useful for stratifying patients with SCLC for treatment approaches. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: Age < 65 years old, ECOG score < 2 points, LD-SCLC, and pretreatment LDH <215.70 U/L are the positive independent prognostic factors for SCLC patients. WHAT THIS STUDY ADDS: The current study provided more references for SCLC diagnosis and treatment and determined more factors for stratifying patients with SCLC for treatment approaches.

N6-methyladenosine reader YTHDC2 and eraser FTO may determine hepatocellular carcinoma prognoses after transarterial chemoembolization.

Transarterial chemoembolization (TACE) has significantly improved overall survival (OS) of unresectable hepatocellular carcinoma (HCC) patients. Unfortunately, a portion of patients show no therapeutic responses to TACE. N6-methyladenosine (m6A) as well as its epigenetic writers, erasers, and readers play a crucial role in HCC development. However, it is still largely unclear how functional small nucleotide polymorphisms (SNPs) in m6A-regulating genes contribute to prognosis of TACE-treated HCC patients. In this study, potential functional SNPs were systematically evaluated to identify their roles in the prognosis of HCC patients after TACE in a Chinese Han population. Employing multiple databases, we successfully annotated 55 candidate SNPs. After genotyping these SNPs in our TACE cohort, we identified three genetic variants in YTHDC2 (rs6594732, rs10071816, and rs2303718) and one SNP in FTO (rs7202116) having statistically significant associations with the OS of HCC patients treated with TACE. For example, multivariate Cox proportional hazards model indicated that the rs7202116 GG genotype carriers had markedly shorter OS and an 87% increased death risk compared with the AA carriers after TACE therapy (P = 0.002). When investigating functional relevance of these SNPs, we observed an allelic regulation of rs7202116 on FTO expression in HCC tissue samples, with higher tumor suppressor FTO expression among the A allele carriers. Our findings reported the first evidence supporting the prognostic value of m6A reader YTHDC2 and m6A eraser FTO SNPs in TACE-treated HCC patients. Importantly, our data implicated that m6A-regulating genes may be targets to improve therapeutic strategy for unresectable HCC patients.

Blood cell parameters as prognostic predictors of disease development for patients with advanced non-small cell lung cancer.

Although the prognostic value of the neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR) and lymphocyte/white blood cell ratio (LWR) has been described in advanced non-small cell lung cancer (NSCLC), the association between complete blood cell parameters prior to disease treatment and NSCLC have yet to be identified. The aim of the present study was to assess the complete blood cell parameters prior to disease treatment in patients with advanced NSCLC. A total of 268 patients with advanced NSCLC were enrolled in this study. Clinical and laboratory data of the patients were acquired through medical records. Receiver operating characteristic curve analysis was used to determine the optimal cut-off values of the neutrophil/white blood cell ratio (NWR), NLR, platelet/white blood cell ratio (PWR), PLR, monocyte/white blood cell ratio (MWR), monocyte/lymphocyte ratio (MLR) and LWR. Kaplan-Meier univariate and multivariate Cox regression analyses were used to evaluate the effect of complete blood parameters on progression-free survival (PFS) and overall survival (OS). The optimal cut-off values were identified as 0.67 for NWR, 2.85 for NLR, 37.23 for PWR, 166.56 for PLR, 0.074 for MWR, 0.31 for MLR and 0.24 for LWR. Univariate analysis revealed that sex (P=0.038), histological type (P<0.0001), NWR (P=0.026), NLR (P=0.044) and MLR (P=0.012) were all associated with PFS, whereas histological type (P=0.003), NWR (P=0.003), NLR (P=0.015), MLR (P=0.006) and LWR (P=0.043) were significantly associated with OS in patients with advanced NSCLC. Histological type (P=0.002) was an independent prognostic factor for PFS in patients with advanced NSCLC. Whereas histological type (P=0.005), NWR (P=0.005), NLR (P=0.014), MLR (P=0.006), and LWR (P=0.034) were independent prognostic factors for OS. Taken together, the present study identified high NWR, NLR and MLR, and low LWR as independent prognostic factors for poor OS in patients with NSCLC.

Role of long non-coding RNA in drug resistance in non-small cell lung cancer.

Lung cancer is the leading cause of cancer-associated death, and non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancer cases. Many drugs have been used to treat NSCLC in order to improve patient prognosis. Platinum-based chemotherapy is the first-line treatment for locally advanced or metastatic patients. For patients with activating EGFR mutations, tyrosine kinase inhibitors are the best treatment choice. NSCLC initially exhibits an excellent response to treatment; however, acquired resistance has been observed in many patients, leading to ineffective treatment. Clinical resistance is an impediment in the treatment of patients with advanced NSCLC. Many sequencing technologies have shown that long non-coding RNA (lncRNA) is expressed differently between drug-resistant and drug-sensitive lung cancer cells. We review the literature on lncRNA in drug resistance of NSCLC. The aim of this review is to gain insight into the molecular mechanisms of drug resistance, mainly focusing on the role of lncRNA in NSCLC.