Immune regulation and the tumor microenvironment in anti-PD-1/PDL-1 and anti-CTLA-4 therapies for cancer immune evasion: A bibliometric analysis.

This study aims to conduct a bibliometric analysis, employing visualization tools to examine literature pertaining to tumor immune evasion related to anti-CTLA-4 and anti-PD-1/PD-L1 therapy from 1999 to 2022. A special emphasis is placed on the interplay between tumor microenvironment, signaling pathways, immune cells and immune evasion, with data sourced from the Web of Science core collection (WoSCC). Advanced tools, including VOSviewer, Citespace, and Scimago Graphica, were utilized to analyze various parameters, such as co-authorship/co-citation patterns, regional contributions, journal preferences, keyword co-occurrences, and significant citation bursts. Out of 4778 publications reviewed, there was a marked increase in research focusing on immune evasion, with bladder cancer being notably prominent. Geographically, China, the USA, and Japan were the leading contributors. Prestigious institutions like MD Anderson Cancer Center, Harvard Medical School, Fudan University, and Sun Yat Sen University emerged as major players. Renowned journals in this domain included Frontiers in Immunology, Cancers, and Frontiers in Oncology. Ehen LP and Wang W were identified as prolific authors on this topic, while Topalian SL stood out as one of the most cited. Research current situation is notably pivoting toward challenges like immunotherapy resistance and the intricate signaling pathways driving drug resistance. This bibliometric study seeks to provide a comprehensive overview of past and current research trends, emphasizing the potential role of tumor microenvironment, signaling pathways and immune cells in the context of immune checkpoint inhibitors (ICIs) and tumor immune evasion.

Efficacy of adjuvant chemotherapy on overall survival in patients with lymph node-positive esophageal squamous cell carcinoma: Is oral chemotherapy promising?

BACKGROUND: The role of adjuvant chemotherapy in patients with pathological lymph node-positive (pN+) resectable esophageal squamous cell carcinoma (ESCC) remains unclear. We aimed to explore whether adjuvant chemotherapy could improve the overall survival (OS) of patients with pN+ ESCC and whether oral chemotherapy could be used as an alternative to intravenous chemotherapy. METHODS: The patients were divided into two groups: a surgery plus chemotherapy group (S + CT group, 400 patients) and a surgery alone group (S group, 582 patients). Propensity score matching (PSM) was used to create patient groups that were balanced across several covariates (n = 331 in each group). The survival rates of patients receiving oral chemotherapy (69 patients with S-1 and 68 patients with tegafur tablets) and intravenous chemotherapy (263 patients) were compared using the Kaplan-Meier method. RESULTS: In the overall study cohort, the 3-year OS was significantly higher in the S + CT group than in the S group (66.3% vs. 49.9%, p < 0.001). These data were confirmed in the matched groups (3-year OS, 72.9% vs. 62.0%, p < 0.001). Multivariate Cox regression analysis in the matched samples showed that adjuvant chemotherapy was an independent prognostic factor for ESCC (HR: 0.62, 95% CI: 0.50-0.76, p < 0.001). Patients who received oral chemotherapy had a similar OS as patients who received intravenous chemotherapy. CONCLUSIONS: Adjuvant chemotherapy could significantly improve the OS of patients with pN+ ESCC, and oral chemotherapy drugs might be a better option because of their similar efficacy but fewer side effects than intravenous chemotherapy. This conclusion warrants further study in prospective, randomized controlled trials.

Impacts of neoadjuvant chemoradiotherapy on the immune landscape of esophageal squamous cell carcinoma.

BACKGROUND: Neoadjuvant chemoradiotherapy (neoCRT) followed by surgery is the most common approach for locally advanced resectable esophageal squamous cell carcinoma (ESCC) patients. How neoCRT impacts ESCC tumor immune microenvironment (TIME) has not been fully understood. METHODS: Single-cell RNA sequencing (scRNA-seq) was conducted to examine the neoCRT-driven cellular and molecular dynamics in 8 pre- and 7 post-neoCRT ESCC samples from 8 male patients. FINDINGS: scRNA-seq data of about 112,000 cells were obtained. Expression programs of cell cycle, epithelium development, immune response, and extracellular structure in pre-treatment tumor cells were related to neoCRT response. Spearman correlation between CD8+ T cells' cytotoxicity and expression of checkpoint molecules was prominent in pre-neoCRT intermediate activated/exhausted CD8+ T cells. NeoCRT increased CD8+ T cells' infiltration but promoted their exhaustion in both major and minor responders. NeoCRT promoted differentiation of Th but demoted that of Treg cells in major responders. Maturation of cDC1s and expression of M2 macrophage markers increased while the number of cDC2s decreased after neoCRT. Higher activities of immune-related pathways in pre-neoCRT CD8+ T cells and macrophages, as well as a pronounced decrease of them after neoCRT, correlated with better neoCRT response. Interactions between intermediate activated/exhausted CD8+ T and macrophages, cDC1s, and LAMP3+ cDCs decreased after neoCRT. INTERPRETATION: Our comprehensive picture of the neoCRT-related immune changes provides deeper insights into immunological mechanisms associated with ESCC response to neoCRT, which may aid in future development of immune-strategies for improving ESCC treatment. FUNDING: This work was supported by the National Natural Science Foundation of China (82072607).

BCL6-SPECC1L: A Novel Fusion Gene in Nasopharyngeal Carcinoma.

Background: Nasopharyngeal carcinomas (NPCs) are malignant tumors originating from the lining epithelium of the nasopharynx. Fusion genes have been confirmed to play important roles in the occurrence and development of various malignant tumors, but the role of fusion genes in NPC is poorly understood. We aimed to explore new fusion genes that promote the occurrence and development of NPC. Methods: RNA-seq was used to search for interchromosomal translocations in 18 NPC tissues. Polymerase chain reaction (PCR) and Sanger sequencing were applied to verify the presence of BCL6-SPECC1L (BS); quantitative PCR (qPCR) and Western blotting were used to measure the expression level of BCL-6 in NPC cells; MTT and in vivo tumorigenesis assays were applied to evaluate the cell proliferation ability; immunofluorescence assays were used to determine the cellular localization of BCL6 and BS; and a luciferase reporter assay was performed to evaluate the ability of BCL6 and BS to inhibit transcription. Results: BS was present in 5.34% (11/206) of primary NPC biopsies and 2.13% (1/47) of head and neck cancer biopsies. The expression of BCL6 was downregulated in NPC, and silencing of endogenous BCL6 promoted NPC cell proliferation in vitro. Overexpression of BCL6 but not BS inhibited the growth of NPC cells in vivo and in vitro. Mechanistically, BCL6 localized in the nucleus can inhibit the G1/S transition to suppress the growth of NPC cells. However, after the fusion of BCL6 and SPECC1L, the product cannot localize to the nucleus, and the transcriptional inhibitory function of BCL6 is abolished, eventually abolishing its tumor suppressor effect and leading to the development of NPC. Conclusion: BS is a novel fusion gene in NPC that may play an important role in the occurrence and development of this cancer. The clinical significance of the BS fusion gene needs further elucidation.

Inactivation of Hippo pathway characterizes a poor-prognosis subtype of esophageal cancer.

Identification of molecular subtypes that reflect different prognoses and treatment responses, especially immune checkpoint inhibitors (ICIs) in esophageal squamous cell carcinoma (ESCC), is essential for treatment decisions. We performed targeted sequencing in 201 patients with ESCC to discover genetic subtypes and validate our findings via multiple data sets. We identified 3 driver genes (FCGBP, GRIN2B, and FRY), and recurrent truncating mutations in FRY impaired its tumor-suppressive function and promoted tumor proliferation. A 3-gene mutation signature (FAT1, FAT3, and FRY) recognized a molecular subtype named "FAT/FRY" with frequent Hippo pathway-related mutations. In multiple ESCC cohorts, the patients with the FAT/FRY subtype had poorer prognosis than did patients in the WT group. Transcriptome analysis indicated that the FAT/FRY subtype was characterized by inactivation of the Hippo pathway, hypoxia, chemoresistance, higher infiltration of CD8+ T cells and activated DCs, and a transcriptome similar to that of cancer responders. Furthermore, the 3-gene signature predicted better survival for patients treated with ICIs, partially explained by its positive correlation with the tumor mutation burden and neoantigen burden. The 3-gene signature is a biomarker to recognize the FAT/FRY molecular subtype, evaluate prognosis, and select potential beneficiaries of ICIs in ESCC.

Development and Validation of Survival Nomograms in Patients with Primary Bladder Lymphoma.

BACKGROUND: The existing studies on primary bladder lymphoma (PBL) are retrospective analyses based on individual cases or small series studies, and the research on PBL is not unified and in-depth enough at present because of the scarcity of PBL and the lack of relevant literature. This study is designed to develop and validate nomograms for overall survival (OS) and cancer-specific survival (CSS) prediction in patients with PBL. METHODS: According to the Surveillance, Epidemiology, and End Results (SEER) database, 405 patients diagnosed with PBL from 1975 to 2016 were collected and randomly assigned to training (n = 283) and validation (n = 122) cohort. After the multivariable Cox regression, the OS and CSS nomograms were developed. The discrimination, calibration and clinical usefulness of the nomograms were assessed and validated, respectively, by the training and validation cohort. Furthermore, all of the patients were reclassified into high- and low-risk groups and their survival were compared through Kaplan-Meier method and log-rank test. RESULTS: Age, subtype, Ann Arbor stage, radiation and chemotherapy were identified as independent prognostic factors for OS and age, sex, and subtype for CSS, then corresponding nomograms predicting the 3- and 5-year survival were constructed. The presented nomograms demonstrated good discrimination and calibration, which the C-index in the training and validation cohort were 0.744 (95% confidence interval [CI], 0.705-0.783) and 0.675 (95% CI, 0.603-0.747) for OS nomogram and 0.692 (95% CI, 0.632-0.752) and 0.646 (95% CI, 0.549-0.743) for CSS nomogram, respectively. Furthermore, the nomograms can be used to effectively distinguish Patients with PBL at high risk of death. The clinical usefulness of the nomograms was visually displayed by decision curve analysis. CONCLUSION: We updated the baseline characteristics of patients with PBL and constructed OS and CSS nomograms to predict their 3- and 5-year survival. Using these nomograms, it would be convenient to individually predict the prognosis of patients with PBL and provide guidance for clinical treatment.

Integration of Tumor Heterogeneity for Recurrence Prediction in Patients with Esophageal Squamous Cell Cancer.

Esophageal squamous cell carcinoma (ESCC) is one of the deadliest malignancies in China. The prognostic value of mutations, especially those in minor tumor clones, has not been systematically investigated. We conducted targeted deep sequencing to analyze the mutation status and the cancer cell fraction (CCF) of mutations in 201 ESCC patients. Our analysis showed that the prognostic effect of mutations was relevant to the CCF, and it should be considered in prognosis prediction. EP300 was a promising biomarker for overall survival, impairing prognosis in a CCF dose-dependent manner. We constructed a CCF-based predictor using a smooth clipped absolute deviation Cox model in the training set of 143 patients. The 3-year disease-free survival rates were 6.3% (95% CI: 1.6-23.9%), 29.8% (20.9-42.6%) and 70.5% (56.6-87.7%) in high-, intermediate- and low-risk patients, respectively, in the training set. The prognostic accuracy was verified in a validation set of 58 patients and the TCGA-ESCC cohort. The eight-gene model predicted prognosis independent of clinicopathological factors and the combination of our model and pathological staging markedly improved the prognostic accuracy of pathological staging alone. Our study describes a novel recurrence predictor for ESCC patients and provides a new perspective for the clinical translation of genomic findings.

Prognostic impact of sterilized lymph nodes in esophageal squamous cell carcinomas after neoadjuvant chemoradiotherapy.

BACKGROUND: The prognostic importance of sterilized lymph nodes (SLN) remains unclear in patients with esophageal squamous cell carcinomas (ESCC) treated by neoadjuvant chemoradiotherapy (nCRT). This study aimed to determine whether SLN predicted disease-free survival (DFS) in ESCC. METHODS: We enrolled 246 eligible patients who were divided into SLN (+) and SLN (-) group according to the presence or absence of fibrosis, necrosis, calcifications and/or foreign body giant cell reactions in the negative lymph nodes specimens. The prognostic value of SLN was determined using univariate and multivariate analyses. The prognostic strength of counting SLN as positive lymph nodes was evaluated using the difference of Akaike information criterion (ΔAIC). RESULTS: A total of 61 SLN were identified in 38 (15.4%) patients. There was no significant difference in baseline characteristics between SLN (+) and SLN (-) group. The most frequently detected SLN in the thoracic cavity and abdominal cavity were those along bilateral recurrent laryngeal nerve (21/38,55.3%) and left gastric artery (13/24,60.9%), respectively. The univariate and multivariate analyses showed SLN was an independent prognostic factor for worse DFS in the whole cohort (HR = 2.05, 95%CI = 1.08-3.90, P = 0.029). The SLN (+) group additionally correlated with worse 5-year DFS than SLN (-) group in the ypT0, ypN0 and pCR subgroups. Counting SLN as positive lymph nodes showed better prognostic strength than ignoring them. CONCLUSION: SLN was of prognostic significance for worse DFS in patients with ESCC, particularly in patients with good response to nCRT.

Autocrine INSL5 promotes tumor progression and glycolysis via activation of STAT5 signaling.

Metabolic reprogramming plays important roles in development and progression of nasopharyngeal carcinoma (NPC), but the underlying mechanism has not been completely defined. In this work, we found INSL5 was elevated in NPC tumor tissue and the plasma of NPC patients. Plasma INSL5 could serve as a novel diagnostic marker for NPC, especially for serum VCA-IgA-negative patients. Moreover, higher plasma INSL5 level was associated with poor disease outcome. Functionally, INSL5 overexpression increased, whereas knockdown of its receptor GPCR142 or inhibition of INSL5 reduced cell proliferation, colony formation, and cell invasion in vitro and tumorigenicity in vivo. Mechanistically, INSL5 enhanced phosphorylation and nuclear translocation of STAT5 and promoted glycolytic gene expression, leading to induced glycolysis in cancer cells. Pharmaceutical inhibition of glycolysis by 2-DG or blockade of INSL5 by a neutralizing antibody reversed INSL5-induced proliferation and invasion, indicating that INSL5 can be a potential therapeutic target in NPC. In conclusion, INSL5 enhances NPC progression by regulating cancer cell metabolic reprogramming and is a potential diagnostic and prognostic marker as well as a therapeutic target for NPC.

Clinical characteristics and prognostic value of pre-retreatment plasma epstein-barr virus DNA in locoregional recurrent nasopharyngeal carcinoma.

PURPOSE: To define the clinical characteristics and prognostic value of pre-retreatment plasma Epstein-Barr virus (EBV) DNA, we investigated EBV status in locoregional recurrent nasopharyngeal carcinoma (lrNPC) patients. METHODS: Between April 2008 and August 2016, the data of patients with nonmetastatic lrNPC were retrospectively reviewed. The survival indexes of patients between different pre-retreatment EBV status groups were compared. RESULTS: A total of 401 patients with nonmetastatic lrNPC were enrolled, and 197 (49.1%) patients had detectable pre-retreatment plasma EBV DNA. Treatment included radiotherapy alone (n = 37 patients), surgery alone (n = 105), radiotherapy (n = 208), surgery combined with radiotherapy (n = 20), chemotherapy and targeted therapy (n = 31). Median follow-up was 32 months. The 3-year locoregional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS), and overall survival (OS) rates for the entire cohort were 64.8%, 89.4%, and 58.8%, respectively. The estimated 3-year LRRFS, DMFS, and OS rates for the pre EBV-positive group vs the pre EBV-negative group were 54.2% vs 75.0% (P < 0.001), 86.6% vs 91.9% (P = 0.05), 51.6% vs 65.9% (P = 0.01), respectively. Among patients in the clinical stage rI/II, there were 17 patients in the radiotherapy alone group and 49 patients in the surgery alone group. And there was no significant difference in overall survival between radiotherapy and surgery, even among the different pre-EBV statuses (P > 0.05). In terms of long-term toxic and side effects, the incidence of radioactive temporal lobe injury in the radiotherapy group was higher than that in the surgery group (35.3% vs 8.2%, P < 0.001), and no statistically significant difference was found in other long-term toxic and side effects. CONCLUSIONS: The positive rate of pre-retreatment plasma EBV DNA in lrNPC is lower than primary NPC. The prognosis of EBV DNA negative group is better than positive group. For locally early-stage lrNPC, regardless of EBV DNA status, radiotherapy and surgery are available options and both can achieve better long-term survival.