Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, China. The authors have no conflicts of interest to declare.
Cancer immunotherapy has produced impressive clinical results in recent years. Despite the success of the checkpoint blockade strategies targeting cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death receptor 1 (PD-1), a large portion of cancer patients have not yet benefited from this novel therapy. T cell immunoglobulin and mucin domain 3 (TIM-3) has been shown to mediate immune tolerance in mouse models of infectious diseases, alloimmunity, autoimmunity, and tumor Immunity. Thus, targeting TIM-3 emerges as a promising approach for further improvement of current immunotherapy. Despite a large amount of experimental data showing an immune suppressive function of TIM-3 in vivo, the exact mechanisms are not well understood. To enable effective targeting of TIM-3 for tumor immunotherapy, further in-depth mechanistic studies are warranted. These studies will also provide much-needed insight for the rational design of novel combination therapy with other checkpoint blockers. In this review, we summarize key evidence supporting an immune regulatory role of TIM-3 and discuss possible mechanisms of action.
Chronic obstructive pulmonary disease ( COPD ) is associated with systemic effects, and T ‐cell‐mediated immunity was involved in the COPD . COPD A ssessment T est ( CAT ) could provide a valid, reliable, and standardized measure of COPD health status. The objective of this study was determination of lymphocyte subpopulation in patients with stable COPD ( n = 52) and to ascertain if a relationship existed between T ‐lymphocyte subpopulation and CAT performance. The stable COPD patients were assessed with CAT , and divided into four groups with score >30 ( n = 8), 20< score ≤30 ( n = 16), 10< score ≤20 ( n = 20), and score ≤10 ( n = 8). Spearman's rank correlation was used to determine the relationship between proportion of T lymphocyte and CAT score. We found an elevated proportion of CD 8 + cells in COPD patients of the group with score >30 compared to other groups. Proportion of CD 4 + cells was significantly lower in the groups with score >30 and 20< score ≤30 when compared to groups with 10< score ≤20 and score ≤10. The CD 4 + : CD 8 + ratio was also significantly lower in the groups with score >30 and 20< score ≤30. Of note are the correlations of proportion of CD 8 + cells and CD 4 + : CD 8 + ratio with CAT performance when score >20. No correlations existed between proportion of CD 4 + , CD 8 + cells, CD 4 + : CD 8 + ratio, and CAT performance when score ≤20. Our results show that the determinants of T ‐lymphocyte subpopulation in COPD patients were value to assess physical conditions. We considered CD 4 + and CD 8 + T lymphocytes to be a representative and stable parameter in grading of health status in COPD patients.
3124 Background: Recognition of tumor neoantigen is the key to generating immune response. The expression and integrity of human leukocyte antigen (HLA) are the prerequisites for neoantigen presentation, and loss of heterozygosity in HLA (HLA LOH) may facilitate immune evasion. However, the incidence of HLA LOH in Chinese cancer patients is unknown. Methods: In this study, 45 samples sequenced with both 1021-gene panel and whole-exome sequencing(WES) were used to evaluate the consistency of HLA LOH in the two testing strategies. The prevalence of HLA LOH analysis was performed in 1546 advanced patients across 10 diverse cancer types and 114 early-stage lung cancer patients who had undergone tumor profiling using 1021-gene panel. Exon 2, exon 3 and bilateral introns of HLA-A/B/C genes were well covered in 1021-gene panel. HLA LOH were analysis using LOHHLA algorithm (McGranahan, et al. 2017). Results: In the HLA LOH analysis of 45 samples, the consistency of 1021-gene panel and WES was 95.6% (43/45). Among the 1660 samples, 1.3% (21) were detected as HLA homozygous at all of the three site. HLA LOH was found in 45.1%(697/1546) of all the advanced patients, range from 24.1% to 59.7%. In colorectal cancer, the HLA LOH ratio of MSS samples was significantly higher than that of MSI-H samples (46.2%, 61/132 vs 16.7%, 3/18 p =0.0214). For NSCLC, the proportion of HLALOH in early-stage (I-IIIa) lung adenocarcinoma and lung squamous cell carcinoma was 25.7% (18/70) and 65.9% (29/44), respectively, consistent with the report. However, advanced (IIIa-IV) lung adenocarcinoma and lung squamous cell carcinoma were 49.4%(168/340) and 58.7%(179/305), respectively. The reason for the difference between early-stage lung adenocarcinoma and advanced lung adenocarcinoma needs further study. In 43.8% of cases (326/744), LOH occurred simultaneously in HLA-A, B and C,suggesting that the Class I locus was often lost together. Conclusions: We can use multi-gene panel for HLA LOH analysis, provided that the relevant regions are well captured. The prevalenceof HLA LOHpresent differences among cancer types.Understanding these distributions may provide more information for immunotherapy research. [Table: see text]
<div>Abstract<p>Chronic obstructive pulmonary disease (COPD) is a long-term lung disease characterized by irreversible lung damage resulting in airflow limitation, abnormal permanent air-space enlargement, and emphysema. Cigarette smoking is the major cause of COPD with 15% to 30% of smokers developing either disease. About 50% to 80% of patients with lung cancer have preexisting COPD and smokers who have COPD are at an increased risk for developing lung cancer. Therefore, COPD is considered an independent risk for lung cancer, even after adjusting for smoking. A crucial early event in carcinogenesis is the induction of the genomic instability through alterations in the mitotic spindle apparatus. To date, the underlying mechanism by which COPD contributes to lung cancer risk is unclear. We hypothesized that tobacco smoke carcinogens induce mitotic spindle apparatus abnormalities and alter expression of crucial genes leading to increased genomic instability and ultimately tumorigenesis. To test our hypothesis, we assessed the genotoxic effects of a potent tobacco-smoke carcinogen [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, (NNK)] on bronchial epithelial cells from patients with COPD and normal bronchial epithelial cells and identified genes associated with mitotic spindle defects and chromosome missegregation that also overlap with lung cancer. Our results indicate that exposure to NNK leads to a significantly altered spindle orientation, centrosome amplification, and chromosome misalignment in COPD cells as compared with normal epithelial cells. In addition, we identified several genes (such as <i>AURKA</i>, <i>AURKB</i>, and <i>MAD2L2</i>) that were upregulated and overlap with lung cancer suggesting a potential common pathway in the transition from COPD to lung cancer.</p></div>
Abstract Lung cancer is recognized as the leading cause of cancer-related death worldwide, with non-small cell lung cancer (NSCLC) being the predominant subtype, accounting for approximately 85% of lung cancer cases. Although great efforts have been made to treat lung cancer, no proven method has been found thus far. Considering β, β-dimethyl-acryl-alkannin (ALCAP2), a natural small-molecule compound isolated from the root of Lithospermum erythrorhizon. We found that lung adenocarcinoma (LUAD) cell proliferation and metastasis can be significantly inhibited after treatment with ALCAP2 in vitro, as it can induce cell apoptosis and arrest the cell cycle. ALCAP2 also significantly suppressed the volume of tumours in mice without inducing obvious toxicity in vivo. Mechanistically, we revealed that ALCAP2-treated cells can suppress the nuclear translocation of β-catenin by upregulating the E3 ligase NEDD4L, facilitating the binding of ubiquitin to β-catenin and eventually affecting the wnt-triggered transcription of genes such as survivin, cyclin D1, and MMP9. As a result, our findings suggest that targeting the oncogene β-catenin with ALCAP2 can inhibit the proliferation and metastasis of LUAD cells, and therefore, ALCAP2 may be a new drug candidate for use in LUAD therapeutics.
Gefitinib is currently the preferred treatment for non‑small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR)‑activating mutation. However, some patients gradually develop acquired resistance after receiving treatment. In addition to secondary T790M mutation, the remaining mechanisms contributing to non‑T790M mutations need to be explored. In the present study, NSCLC‑derived HCC827 and PC‑9 cells and the corresponding gefitinib‑resistant cell lines (HCC827GR and PC9GR) were utilized. Next‑generation DNA sequencing was performed on the HCC827GR and PC9GR cells. Under AXL receptor tyrosine kinase (AXL) knockdown or miR‑625‑3p overexpressing conditions, a cell growth inhibition assay was performed to evaluate gefitinib sensitivity. Wound healing and Transwell assays were used to examine the migratory and invasive abilities of the cells. Moreover, we also carried out western blot analysis to detect the altered downstream signaling pathway. Our study revealed markedly decreased miR‑625‑3p expression in the HCC827GR cell line, while its overexpression partly reversed gefitinib resistance. Integrated analysis based on Targetscan website showed that AXL can be potentially targeted by miR‑625‑3p and we further verified the hypothesis via dual‑luciferase reporter assays. Mechanistic analysis revealed that TGF‑β1‑induced EMT may contribute to the miR‑625‑3p/AXL axis‑mediated gefitinib resistance. Our data demonstrated that miR‑625‑3p contributes to the acquired resistance of gefitinib, which may provide novel insight to combat resistance to EGFR‑TKIs.
Immunotherapy that inhibits the interaction between programmed death ligand 1 (PD-L1), present on the surface of tumor or antigen-presenting cells, and programmed death 1 (PD-1), present on the surface of activated lymphocytes, is generating much excitement and enthusiasm. Although considerable knowledge has been accumulated on anti-PD-L1 and anti-PD-1 reagents, discovering immunotherapy-associated issues still remains a pressing task for the researchers and clinicians.
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