PD‐1 is highly expressed on tumor‐infiltrated antigen‐specific T cells and limit the antitumor function. Blocking of PD‐1/PD‐L1 signaling has shown unprecedented curative efficacies in patients with advanced cancer. However, only a limited population of patients benefited from such therapies. Our study aimed to explore biological properties, functional regulation and reversal of MAGE‐A3‐specific CD8+ T cells in patients with esophageal squamous cell carcinoma (ESCC). The underlying principle of deficiency and restoring MAGE‐A3‐specific CD8+ T cells function in tumor microenvironment (TME) was evaluated. MAGE‐A3‐specific CD8+ T cells could lyse HLA‐A2+/MAGE‐A3+ tumor cells. Tetramer+ T cell frequency was higher in elder patients, but lower in patients with lymph node metastasis and late tumor stage (p < 0.05). CD107ahigh expression on functional T cells was an independent prognostic factor in Cox regression analysis. PD‐1 was highly expressed on dysfunctional antigen‐specific CD8+ T cells and tumor infiltrating T lymphocytes (p < 0.05). Myeloid‐derived suppressor cells (MDSCs) derived‐TGF‐β mediated PD‐1high expression on CD8+ T cells, which led to be resistance to PD‐1/PD‐L1 blockade in TME. Dual PD‐1/PD‐L1 and TGF‐β signaling pathway blockades synergistically restored the function and antitumor ability of antigen‐specific CD8+ T cells in vitro/vivo assay. The presence of functional MAGE‐A3‐specific CD8+ T cells had an independent prognostic impact on survival of patients with ESCC. Furthermore, MDSCs‐derived TGF‐β increased PD‐1 expression on T cells and decreased the sensitivity to PD‐1/PD‐L1 blockade. Combining T cell‐based therapy with dual PD‐1/PD‐L1 and TGF‐β signaling pathway blockade could be considered a promising strategy for cancer treatment.
() is a novel cancer/testis-associated gene, which is not only expressed in the male testicular germ cells among human normal tissues, but is also aberrantly expressed in various cancer tissues. In our study, was characterized as a tumor-promoting gene and was significantly associated with esophageal squamous cell carcinoma (ESCC) recurrence and unfavorable prognosis. Kaplan-Meier analysis showed that patients with high expression had a shorter survival time. Functional experiments showed that promoted tumor cell growth and inhibited cell apoptosis. These results prompted us to investigate the factors affecting the tumorigenicity of Further experimentation demonstrated that enhanced the expression of phosphorylated Akt1, with subsequent phosphorylation of nuclear factor kappa B (NF-κB) subunit RelA in tumor cells, and chemoattracted myeloid-derived suppressor cells (MDSCs) by upregulating interleukin-8 (IL8) to accelerate tumor progression in the tumor microenvironment. We also found that TGFβ secreted by MDSCs could upregulate by inducing Smad2/Smad3 phosphorylation. In summary, this study revealed a mechanism by which could upregulate IL8 through Akt1/RelA to direct MDSCs homing into the tumor, suggesting that could be an attractive therapeutic target and a prognostic marker against ESCC. .
Background: A number of mutations in key oncogenes have been identified as important for the initiation and maintenance of lung adenocarcinoma (LAC). This study elucidated the prevalence and prognostic significance of mutations in the epidermal growth factor receptor gene (EGFR) and rearrangements in the anaplastic lymphoma kinase gene (ALK) in patients with surgically resected primary LAC.Patients and Methods: We retrospectively analyzed 675 consecutive patients who underwent radical resection at a single institution. We concurrently analyzed mutations in EGFR and the Kirsten rat sarcoma viral oncogene homolog gene (KRAS) by reverse transcription (RT)-PCR, and investigated ALK rearrangements by immunohistochemistry. LAC with or without various oncogenic mutations was studied for clinicopathological features and their association with disease-free survival (DFS) and overall survival (OS).Result: ALK rearrangements and EGFR mutations were detected in 75 and 312 patients, respectively, with coexistence in 5 cases. ALK rearrangements and mutations in EGFR and KRAS were mutually exclusive. Compared with patients with EGFR mutations, ALK rearrangements were more common in younger patients, and those with advanced tumors, lymph node metastases, and higher rates of postoperative adjuvant therapy. Histologically, EGFR mutations were more common than ALK rearrangements in patients with the acinar predominant subtype and the lepidic predominant subtype of LAC, whereas ALK rearrangements were more frequent in the solid predominant subtype with mucin production and invasive mucinous adenocarcinomas. ALK-positive patients had a significantly worse DFS than those with EGFR mutations and wild-type (WT) patients. The mean OS after surgical procedures was significantly longer in EGFR-mutated versus WT patients. No significant differences were found in patients with ALK-positive tumors compared with EGFR-mutated and WT patients.Conclusion: Clinicopathological features of LAC with ALK rearrangements differ from those of LAC with EGFR mutations. Patients with ALK rearrangements had a significantly worse DFS than those harboring EGFR mutations. Thus, ALK rearrangements are an adverse prognostic factor in surgically-resected LAC patients, while EGFR mutations are associated with a better prognosis.
IntroductionThis study determined the prevalence of anaplastic lymphoma kinase (ALK) rearrangement, and identified the associations of ALK rearrangement with clinicopathologic characteristics and treatment outcomes in patients with surgically-resected stage I-III lung adenocarcinoma.MethodsA total of 534 surgically-resected lung adenocarcinoma patients were studied. The prevalence of ALK protein over-expression was determined by a fully-automated immunochemistry assay (with mouse monoclonal Ventana D5F3 antibody), and the associations of ALK rearrangement with clinicopathologic characteristics and treatment outcomes were analyzed.ResultsForty-two (7.9%) of the 534 lung adenocarcinoma patients were ALK IHC-positive. ALK rearrangement was significantly associated with younger age (P = 0.011), high T-stage (P = 0.025), high pathologic stage (P = 0.002), solid predominant adenocarcinoma with mucin production (P = 0.006), invasive mucinous adenocarcinoma (P = 0.009), and receipt of adjuvant therapy after surgery (P = 0.036), but no significant associations were found between the ALK rearrangement and sex or smoking status. ALK IHC-positivity was significantly associated with a shorter disease-free survival, tumor-specific survival, and overall survival (P = 0.001, 0.026, and 0.007, respectively). Multivariate analysis showed that ALK IHC-positivity was an adverse prognostic factor for disease-free survival (HR, 1.80; 95% CI 1.18-2.77; P = 0.007), tumor-specific survival (HR, 2.59; 95% CI 1.35-4.97; P = 0.004), and overall survival (HR, 1.92; 95% CI 1.07-3.44; P = 0.030).ConclusionThe clinical characteristics of patients with ALK-positive lung adenocarcinoma were similar to those of EGFR-mutated patients. ALK rearrangement was an adverse prognostic factor in surgically-resected lung adenocarcinoma patients.
Esophageal cancer (EC) is one of the most common digestive malignant tumors worldwide. Over the past decades, there have been minimal improvements in outcomes for patients with EC. New targets and novel therapies are needed to improve outcomes for these patients. This study aimed to explore the molecular mechanisms of EC by integrated bioinformatic analyses of the feature genes associated with EC and correlative gene functions which can distinguish cancerous tissues from non-cancerous tissues. Gene expression profile GSE20347 was downloaded from Gene Expression Omnibus (GEO) database, including 17 EC samples and their paired adjacent non-cancerous samples. The differentially expressed genes (DEGs) between EC and normal specimens were identified and then applied to analyze the GO enrichment on gene functions and KEGG pathways. Corresponding Pathway Relation Network (Pathway-net) and Gene Signal Network (signal-net) of DEGs were established based on the data collected from GCBI datasets. The results showed that DEGs mainly participated in the process of cell adhesion, cell proliferation, survival, invasion, metastasis and angiogenesis. Aberrant expression of PTK2, MAPK signaling pathway, PI3K-Akt signaling pathway, p53 signaling pathway and MET were closely associated with EC carcinogenesis. Importantly, Interleukin 8 (IL8) and C-X-C chemokine receptor type 7 (CXCR-7) were predicted to be significantly related to EC. These findings were further validated by analyzing both TCGA database and our clinical samples of EC. Our discovery provides a registry of genes and pathways that are disrupted in EC, which has the potential to be used in clinic for diagnosis and target therapy of EC in future.
A 47‐year‐old female with ALK‐rearranged lung adenocarcinoma developed leptomeningeal metastasis (LM) after progression on first‐line crizotinib. Alectinib 300 mg was commenced and the patient achieved clinical and radiographic improvements. After nine months of alectinib 300 mg, she started to experience symptomatic LM. Two concurrent non‐EML4‐ALK rearrangements, LOC388942‐ALK and LINC00211‐ALK, were identified from the CSF but not from the plasma samples. With the primary lung lesions remaining stable, the alectinib dose was increased to 600 mg twice daily which alleviated the clinical symptoms of symptomatic LM. After 7.6 months of alectinib 600 mg, the patient again experienced CNS progression. With both CSF and plasma samples revealing no druggable mutations, the alectinib dose was re‐escalated to 900 mg twice daily, resulting in clinical benefits lasting for two months. Her therapy was then switched to lorlatinib which controlled the disease for 8.7 months until her demise. The LINC00211‐ALK fusion, which retains the ALK kinase domain, detected from the CSF was the mechanism of treatment efficacy in this patient. The central nervous system (CNS) has been increasingly recognized as a site of treatment failure in multiple cancers, including non‐small cell lung cancer (NSCLC). Our case demonstrated that alectinib dose‐escalation and lorlatinib overcame ALK inhibitor resistance in the CNS in an ALK‐positive LM patient. Furthermore, we provide the first clinical evidence of the efficacy of sequential ALK inhibitors in targeting LINC00211‐ALK in a patient with LM.
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