Recent progress in combination therapy of oncolytic vaccinia virus.

In recent years, oncolytic viruses have emerged as promising agents for treating various cancers. An oncolytic virus is a non-pathogenic virus that, due to genetic manipulation, tends to replicate in and cause lysis of cancerous cells while leaving healthy cells unaffected. Among these viruses, vaccinia virus is an attractive platform for use as an oncolytic platform due to its 190 Kb genome with a high capacity for encoding therapeutic payloads. Combining oncolytic VV therapy with other conventional cancer treatments has been shown to be synergistic and more effective than monotherapies. Additionally, OVV can be used as a vector to deliver therapeutic payloads, alone or in combination with other treatments, to increase overall efficacy. Here, we present a comprehensive analysis of preclinical and clinical studies that have evaluated the efficacy of oncolytic vaccinia viruses in cancer immunotherapy. We discuss the outcomes of these studies, including tumor regression rates, overall survival benefits, and long-term responses. Moreover, we provide insights into the challenges and limitations associated with oncolytic vaccinia virus- based therapies, including immune evasion mechanisms, potential toxicities, and the development of resistance.

Discovering single cannabidiol or synergistic antitumor effects of cannabidiol and cytokine-induced killer cells on non-small cell lung cancer cells.

Introduction: A multitude of findings from cell cultures and animal studies are available to support the anti-cancer properties of cannabidiol (CBD). Since CBD acts on multiple molecular targets, its clinical adaptation, especially in combination with cancer immunotherapy regimen remains a serious concern. Methods: Considering this, we extensively studied the effect of CBD on the cytokine-induced killer (CIK) cell immunotherapy approach using multiple non-small cell lung cancer (NSCLC) cells harboring diverse genotypes. Results: Our analysis showed that, a) The Transient Receptor Potential Cation Channel Subfamily V Member 2 (TRPV2) channel was intracellularly expressed both in NSCLC cells and CIK cells. b) A synergistic effect of CIK combined with CBD, resulted in a significant increase in tumor lysis and Interferon gamma (IFN-g) production. c) CBD had a preference to elevate the CD25+CD69+ population and the CD62L_CD45RA+terminal effector memory (EMRA) population in NKT-CIK cells, suggesting early-stage activation and effector memory differentiation in CD3+CD56+ CIK cells. Of interest, we observed that CBD enhanced the calcium influx, which was mediated by the TRPV2 channel and elevated phosphor-Extracellular signal-Regulated Kinase (p-ERK) expression directly in CIK cells, whereas ERK selective inhibitor FR180204 inhibited the increasing cytotoxic CIK ability induced by CBD. Further examinations revealed that CBD induced DNA double-strand breaks via upregulation of histone H2AX phosphorylation in NSCLC cells and the migration and invasion ability of NSCLC cells suppressed by CBD were rescued using the TRPV2 antagonist (Tranilast) in the absence of CIK cells. We further investigated the epigenetic effects of this synergy and found that adding CBD to CIK cells decreased the Long Interspersed Nuclear Element-1 (LINE-1) mRNA expression and the global DNA methylation level in NSCLC cells carrying KRAS mutation. We further investigated the epigenetic effects of this synergy and found that adding CBD to CIK cells decreased the Long Interspersed Nuclear Element-1 (LINE-1) mRNA expression and the global DNA methylation level in NSCLC cells carrying KRAS mutation. Conclusions: Taken together, CBD holds a great potential for treating NSCLC with CIK cell immunotherapy. In addition, we utilized NSCLC with different driver mutations to investigate the efficacy of CBD. Our findings might provide evidence for CBD-personized treatment with NSCLC patients.

Thymic NK-Cells and Their Potential in Cancer Immunotherapy.

Natural killer (NK)-cells are innate immune cells with potent anti-tumor capacity, capable of recognizing target cells without prior exposure. For this reason, NK-cells are recognized as a useful source of cell therapy. Although most NK-cells are derived from the bone marrow (BM), a separate developmental pathway in the thymus also exists, producing so-called thymic NK-cells. Unlike conventional NK-cells, thymic NK (tNK)-cells have a combined capacity for cytokine production and a natural ability to kill tumor cells in the presence of NK-cell receptor stimulatory ligands. Furthermore, tNK-cells are reported to express CD3 subunits intracellularly, without the presence of a rearranged T-cell receptor (TCR). This unique feature may enable harnessing of these cells with a TCR to combine NK- and T-cell effector properties in one cell type. The development, phenotype, and function of tNK-cells, and potential as a cell therapy is, however, poorly explored. In this review, we provide an overview of current literature on both murine and human tNK-cells in comparison to conventional BM-derived NK-cells, and discuss the potential applications of this cellular subset in the context of cancer immunotherapy.

Immunoradiation Therapy for End-Stage Undifferentiated Cervical Cancer That Restored Sensitivity to Chemotherapy and Resulted in the Disappearance of the Cancer.

Among cervical cancers, small cell undifferentiated carcinoma is rare. Because of its rapid progression, the prognosis is extremely poor. During the course of cisplatin-based chemotherapy for stage Ⅳ small cell undifferentiated carcinoma of the cervix, the patient developed drug resistance, and standard treatment was no longer feasible. Therefore, immunoradiotherapy was administered to activate anticancer immunity. Surprisingly, the cancer drug sensitivity was restored, and cisplatin was again successful, and the cancer disappeared. In addition, the activation of cancer-specific immunity maintained the disappearance of the cancer. It should be noted that immunoradiotherapy not only increases anti-cancer immunity but may also contribute to overcoming cancer drug resistance.

The Influence of Drug-Eluting Beads Transarterial Chemoembolization on Serum Levels of Soluble Programmed Cell Death Protein-1 in Advanced Hepatocellular Carcinoma Patients.

Aim: This study aims to explore the role of soluble programmed cell death protein 1 (sPD-1) in individuals with hepatocellular carcinoma (HCC) undergoing treatment with drug-eluting beads transarterial chemoembolization (D-TACE). Additionally, we aim to assess the potential utility of sPD-1 for determining the optimal timing for combining D-TACE with immune checkpoint inhibitors (ICIs). Materials and Methods: A total of 44 HCC patients eligible for D-TACE and 55 healthy volunteers were enrolled in this study. Three milliliters of peripheral venous blood from the patients were collected on the day before D-TACE and 3, 7, and 30 days after D-TACE, respectively, for the assay of sPD-1. The relationships between sPD-1 levels, clinical features, outcomes, and the fluctuation of sPD-1 during treatment were analyzed. Results: The initial sPD-1 levels in patients were found to be significantly higher than those in the control group. Although the initial sPD-1 levels displayed a decreasing trend with an increase in BCLC stage, no significant differences were observed among patients at different BCLC stages. The sPD-1 level on day 3 after D-TACE was similar to that on day 7 after D-TACE and significantly lower than the initial level. The sPD-1 level on day 30 after D-TACE was significantly higher than that on day 3 and day 7 after D-TACE and nearly returned to the initial level before D-TACE. Conclusion: The level of sPD-1 was found to be significantly elevated in patients with HCC. However, further research is deemed necessary to fully understand the role of sPD-1 as a potential biomarker in the initiation, progression, and prognosis of HCC. The decrease in sPD-1 following D-TACE suggests that immune effector cells might potentially be reduced, as well as immune function weakened, highlighting the need to avoid the prompt administration of ICIs after D-TACE.

The prognostic values and immune characteristics of polo-like kinases (PLKs) family: A pan-cancer multi-omics analysis.

Background: In the realm of tumor-targeted therapeutics, Polo-like kinases (PLKs) are a significant group of protein kinases that were found recently as being related to tumors. However, the significance of PLKs in pan-cancer remains systematically studied. Methods and materials: We integrated multi-omics data to comprehensively investigate the expression patterns of the PLK family across various cancer types. Subsequently, study examined the associations between tumor mutation burden (TMB), microsatellite instability (MSI), immune subtype classification, immune infiltration, tumor microenvironment scores, immune checkpoint gene expression, and the PLKs expression profiles within various tumor types. Furthermore, using our mRNA sequencing data (TRUCE01) and four bladder cancer (BLCA) cohorts (GSE111636, GSE176307, and IMvigor210), We examined the correlation between the expression level of PLK and immunotherapy effectiveness. Next, Gene set enrichment analysis (GSEA) was evaluated to find that potentially enriched PLK signaling pathways. Utilizing TIMER 2.0, we conducted an immune infiltration analysis underlying transcriptome expression, copy number variations (CNV), or somatic mutations of PLKs in BLCA. Finally, mRNA expression validation of PLK1/3/4 by real-time PCR within 10 paired BLCA tissues, protein expression verification through the Human Protein Atlas (HPA), and PLK4 in vitro cytological studies have been employed in BLCA. Results: The expression of most of the PLK family members exhibits variation between cancerous tissues and adjacent normal tissues across various cancer species. Furthermore, the expression of PLKs demonstrates a significant association with immunotyping, infiltration of immune cell, tumor mutational burden (TMB), microsatellite instability (MSI), immunological checkpoint gene activity and therapeutic effectiveness in pan-tumor tissues. Additional investigation into the correlation between the PLK family and BLCA has revealed that the expression of the PLK genes holds substantial significance in the biological processes of BLCA. Furthermore, a notable association has been observed between the copy number variation, variant status, and the degree of certain immunological cell infiltration. Of note, the expression validation and in vitro phenotypic experiments have demonstrated that PLK4 has a significant function in promoting the BLCA cell proliferation, migration, and invasion. Conclusion: Collectively, based on various databases, our results highlight the involvement of PLK gene family in the formation of different types of tumors and identify PLK-related genes that may be used for therapy.

Qntrolling the LncRNA HULC-Tregs-PD-1 axis inhibits immune escape in the tumor microenvironment.

Background: Immune escape remains a major challenge in the treatment of malignant tumors. Here, we studied the mechanisms underlying immune escape in the tumor microenvironment and identified a potential therapeutic target. Methods: Pathological specimens from patients with liver cancer, soft tissue sarcoma, and liver metastasis of colon cancer were subjected to immunohistochemistry analysis to detect the expression of programmed death-1 (PD-1) in the tumor microenvironment (TME). Additionally, the expression of regulatory T cells (Tregs) and long non-coding RNAs (lncRNAs), such as highly upregulated in liver cancer (HULC) was evaluated by fluorescence in situ hybridization, and the relationship between HULC, Treg cells, and PD-1 was determined. The animals were divided into H22 hepatic carcinoma and S180 sarcoma groups. Each group was divided into Foxp3-/-C57BL/6J and C57BL/6J mice. Thereafter, mice were inoculated with 0.1 ml S180 sarcoma cells or 0.1 ml H22 hepatoma cells, at a concentration of 1 × 107/ml. The number of splenic CD4+CD25+Foxp3+ T cells was detected by flow cytometry, and serum interleukin-10 (IL-10) and transforming growth factor ß1 (TGF-ß1) levels were detected using a Luminex liquid suspension chip. Expression of PD-1, fork head box P3 (Foxp3), and HULC in the TME, were analyzed and the therapeutic effect of inhibiting the lncRNA HULC-Treg-PD-1 axis in malignant tumors was determined. Results: High expression of lncRNA HULC promotes the proliferation of Treg cells and increases PD-1 expression in the tumor microenvironment. The HULC-Treg-PD-1 axis plays an immunosuppressive role and promotes the proliferation of malignant tumors. Knocking out the Foxp3 gene can affect the HULC-Treg-PD-1 axis and reduce PD-1, IL-10, and TGF-ß1 expression to control the growth of malignant tumors. Conclusion: The lncRNA HULC-Treg-PD-1 axis promotes the growth of malignant tumors. This axis could be modulated to reduce PD-1, IL-10, and TGF-ß1 expression and the subsequent immune escape. The inhibition of immune escape in the tumor microenvironment can be achieved by controlling the LncRNA HULC-Treg-PD-1 axis.

An ion channel-based prognostic model identified TRPV2 and GJB3 as immunotherapy determinants in pancreatic cancer.

Background: Less than 10% of people who have pancreatic ductal adenocarcinoma (PDAC) will survive the malignancy for five years. The ion channel genes-related biomarker and predictive model were needed for exploitation. Methods: Differentially expressed ion channel genes (DEICGs) were detected in PDAC patients. GO and KEGG enrichment analysis was conducted on DEICGs. The prognostic genes were found using Cox regression analysis. After that, a risk model was created and examined. A nomogram was created based on independent predictive analysis. The molecular functions of two risk groups were explored. Immune checkpoint molecule expression was compared in two risk groups. We evaluated the possible cancer immunotherapy response in two risk groups using the TIDE method. We further examined how TRPV2 functions in PDAC as a potent oncogene and regulates the activity of macrophages by in vitro validation, including CCK8, EdU, and Transwell assays. Results: A total of twenty-four DEICGs were found. Next, we discovered that two DEICGs (TRPV2 and GJB3) were connected to PDAC patients' overall survival (OS). The risk model was created and validated, and a nomogram was used to forecast the overall survival of PDAC patients. The high-risk group considerably accumulated oncogenic pathways. Furthermore, we discovered a correlation between the expression of critical immunological checkpoints and the risk score. Furthermore, patients in the high-risk category had a lower chance of benefiting from immune therapy. The HPA database confirmed that TRPV2 is expressed as a protein. Lastly, TRPV2 controls macrophage activity and acts as a potent oncogene in PDAC. Conclusion: Altogether, this study suggested that two ion channel genes, TRPV2 and GJB3, were potential biomarkers for the prognosis of PDAC and immunotherapy targets, and the research will be crucial for creating novel PDAC treatment targets and predictive molecular indicators.

Effectiveness and Safety of Anlotinib Combined with PD-1 Blockades in Patients with Previously Immunotherapy Treated Advanced Non-Small Cell Lung Cancer: A Retrospective Exploratory Study.

Objective: This study aimed to investigate the effectiveness and tolerability of anlotinib plus PD-1 blockades in patients with previously immunotherapy treated advanced non-small-cell lung cancer (NSCLC). Methods: A total of 67 patients with previously immunotherapy treated advanced NSCLC who received anlotinib plus PD-1 blockades in clinical practice were screened retrospectively. All the PD-1 blockades used in this study were approved in China and consisted of sintilimab, camrelizumab, tislelizumab and pembrolizumab. Effectiveness and safety of anlotinib plus PD-1 blockades were assessed, and all patients were followed up regularly. Clinical significance between response status to previous immune-related treatment regimens and therapeutic outcomes of anlotinib plus PD-1 blockades was further explored. Results: The best overall response among the 67 patients suggested that a partial response was observed in 16 patients, stable disease was noted in 41 patients and progressive disease was found in 10 patients, which yielded an objective response rate of 23.9% (95% CI: 14.3-35.9%) and a disease control rate of 85.1% (95% CI: 74.3-92.6%). Prognostic outcomes indicated that the median progression-free survival (PFS) was 6.1 months (95% CI: 2.37-9.83) and the median overall survival (OS) was 16.5 months (95% CI: 10.73-22.27). Exploratory analysis highlighted that patients who were intolerant to previous immune-related regimens (17 patients) might have a superior prognosis (median OS: 22.3 months vs 12.5 months, P=0.024). Additionally, adverse reactions with any grades during anlotinib plus PD-1 blockades administration were observed in 62 patients (92.5%), of which 31 patients (46.3%) had ≥grade 3 adverse reactions. Most common adverse reactions were fatigue, hypertension, diarrhea and hepatotoxicity. Conclusion: Anlotinib plus PD-1 blockades demonstrated promising effectiveness and tolerable safety in patients with previously immunotherapy treated advanced NSCLC. Those who were intolerant to previous immune-related regimens might benefit significantly from treatment with anlotinib plus PD-1 blockades. This conclusion should be confirmed in future studies.

Clinical implications of single cell sequencing for bladder cancer.

Bladder cancer (BC) is the 10th most common cancer worldwide, with about 0.5 million reported new cases and about 0.2 million deaths per year. In this scoping review, we summarize the current evidence regarding the clinical implications of single-cell sequencing for bladder cancer based on PRISMA guidelines. We searched PubMed, CENTRAL, Embase, and supplemented with manual searches through the Scopus, and Web of Science for published studies until February 2023. We included original studies that used at least one single-cell technology to study bladder cancer. Forty-one publications were included in the review. Twenty-nine studies showed that this technology can identify cell subtypes in the tumor microenvironment that may predict prognosis or response to immune checkpoint inhibition therapy. Two studies were able to diagnose BC by identifying neoplastic cells through single-cell sequencing urine samples. The remaining studies were mainly a preclinical exploration of tumor microenvironment at single cell level. Single-cell sequencing technology can discriminate heterogeneity in bladder tumor cells and determine the key molecular properties that can lead to the discovery of novel perspectives on cancer management. This nascent tool can advance the early diagnosis, prognosis judgment, and targeted therapy of bladder cancer.

Codelivery of anti-CD47 antibody and chlorin e6 using a dual pH-sensitive nanodrug for photodynamic immunotherapy of osteosarcoma.

Osteosarcoma is a malignant tumor originating from bone tissue that progresses rapidly and has a poor patient prognosis. Immunotherapy has shown great potential in the treatment of osteosarcoma. However, the immunosuppressive microenvironment severely limits the efficacy of osteosarcoma treatment. The dual pH-sensitive nanocarrier has emerged as an effective antitumor drug delivery system that can selectively release drugs into the acidic tumor microenvironment. Here, we prepared a dual pH-sensitive nanocarrier, loaded with the photosensitizer Chlorin e6 (Ce6) and CD47 monoclonal antibodies (aCD47), to deliver synergistic photodynamic and immunotherapy of osteosarcoma. On laser irradiation, Ce6 can generate reactive oxygen species (ROS) to kill cancer cells directly and induces immunogenic tumor cell death (ICD), which further facilitates the dendritic cell maturation induced by blockade of CD47 by aCD47. Moreover, both calreticulin released during ICD and CD47 blockade can accelerate phagocytosis of tumor cells by macrophages, promote antigen presentation, and eventually induce T lymphocyte-mediated antitumor immunity. Overall, the dual pH-sensitive nanodrug loaded with Ce6 and aCD47 showed excellent immune-activating and anti-tumor effects in osteosarcoma, which may lay the theoretical foundation for a novel combination model of osteosarcoma treatment.

Cabozantinib with immune checkpoint inhibitor versus cabozantinib monotherapy in patients with metastatic clear cell renal cell carcinoma progressing after prior immune checkpoint inhibitor.

INTRODUCTION: Rechallenge with antibodies targeting programmed cell death protein-1 or its ligand (PD-1/L1) after discontinuation or disease progression in solid tumors following a prior PD-1/L1 treatment is often practiced in clinic. This study aimed to investigate if adding PD-1/L1 inhibitors to cabozantinib, the most used second-line treatment in real-world patients with metastatic clear cell renal cell carcinoma (mccRCC), offers additional benefits. METHODS: Using de-identified patient-level data from a large real-world US-based database, patients diagnosed with mccRCC, who received any PD-1/L1-based combination in first-line (1L) setting, followed by second-line (2L) therapy with either cabozantinib alone or in combination with PD-1/L1 inhibitors were included. Patients given a cabozantinib-containing regimen in 1L were excluded. The study end points were real-world time to next therapy (rwTTNT) and real-world overall survival (rwOS) by 2L. RESULTS: Of 12,285 patients with metastatic renal cell carcinoma in the data set, 348 patients met eligibility and were included in the analysis. After propensity score matching weighting, cabozantinib with PD-1/L1 inhibitors versus cabozantinib (ref.) had similar rwTTNT and rwOS in the 2L setting. Hazard ratios and 95% confidence interval (CI) for rwTTNT and rwOS are 0.74 (95% CI, 0.49-1.12) and 1.15 (95% CI, 0.73-1.79), respectively. CONCLUSION: In this study, the results align with the phase 3 CONTACT-03 trial results, which showed no additional benefit of adding PD-L1 inhibitor to cabozantinib compared to cabozantinib alone in 2L following PD-1/L1-based therapies in 1L. These results from real-world patients strengthen the evidence regarding the futility of rechallenge with PD-1/L1 inhibitors.

Electronic health intervention to manage symptoms of immunotherapy in patients with cancer (SOFIA): Results from a randomized controlled pilot trial.

BACKGROUND: For patients receiving immune checkpoint inhibitors, early detection of immune-related adverse events (irAEs) is critical for one's safety. To this end, a smartphone app (SOFIA) was developed that featured the assessment of electronic patient-reported outcomes (ePROs) focusing on irAEs as well as a set of comprehensive supportive information. Its feasibility and preliminary efficacy were evaluated in a randomized controlled trial (RCT). METHODS: Patients who received immune checkpoint inhibition therapy were randomly assigned to an intervention group (IG) or a control group (CG; care as usual). During the 12-week intervention period, IG patients used SOFIA to report twice weekly ePROs and receive cancer- and immunotherapy-relevant contents. Before a patient's next clinical visit, the physician in charge was given the ePRO reports. The primary objective was to test the feasibility of SOFIA. Furthermore, the preliminary efficacy of SOFIA for health-related quality of life (HRQOL), psychosocial outcomes, and medical data was examined. Clinical outcomes were assessed at baseline (T0), post-intervention (T1), and a 3-month follow-up (T2). RESULTS: Seventy-one patients were randomized to the IG (n = 34) or the CG (n = 37). SOFIA showed high feasibility and acceptance. At T1, patients in the IG reported significantly better HRQOL and role functioning and less depression, distress, and appetite loss. No significant differences were revealed regarding medical data, the utilization of supportive care services, or survival. CONCLUSIONS: SOFIA showed high feasibility and acceptance and improved HRQOL and psychosocial outcomes. These results suggest further evaluation of efficacy in a large-scale confirmatory multicenter RCT.

Progression of portal hypertension after atezolizumab plus bevacizumab for hepatocellular carcinoma-report a case and literature review.

BACKGROUND: Atezolizumab/bevacizumab combination therapy became the first-line therapy for advanced hepatocellular carcinoma (HCC). Gastroesophageal varices should be monitored and managed before treatment. The progression of portal hypertension during bevacizumab-containing therapy is unclear. METHOD: A case of new development of esophageal varices, ascites, and hepatic hydrothorax during atezolizumab/bevacizumab therapy at National Taiwan University Hospital was reported, and relevant literature was reviewed. RESULTS: We presented an 83-year-old male with resolved hepatitis B without cirrhosis. He had BCLC stage C HCC and received tri-weekly atezolizumab/bevacizumab therapy for 34 cycles with sustained partial response. Progressive ascites, esophageal varices, and hepatic hydrothorax developed, though his portal vein was patent and the tumor was under control. Five similar cases of HCC (BCLC B/C: n = 3/2) had been reported previously. Among them, three had cirrhosis with pre-existing small esophageal varices before treatment. After the administration of 1-15 cycles of atezolizumab/bevacizumab therapy, one patient had a progression of varices, and the other four developed variceal bleeding. The association between atezolizumab/bevacizumab and portal hypertension was possible, which might relate to the VEGF pathway and immune-related adverse events with progressive hepatic fibrosis. CONCLUSION: Atezolizumab/bevacizumab treatment might exacerbate portal hypertension. Careful monitoring and management should be considered during treatment.

A review on comprehending immunotherapeutic approaches inducing ferroptosis: Managing tumour immunity.

Ferroptosis, a necrotic, iron-dependent controlled cell death mechanism, is distinguished by the development of lipid peroxides to fatal proportions. Malignant tumours, influenced by iron to promote fast development, are vulnerable to ferroptosis. Based upon mounting evidence it has been observed that ferroptosis may be immunogenic and hence may complement immunotherapies. A new approach includes iron oxide-loaded nano-vaccines (IONVs), having supremacy for the traits of the tumour microenvironment (TME) to deliver specific antigens through improving the immunostimulatory capacity by molecular disintegration and reversible covalent bonds that target the tumour cells and induce ferroptosis. Apart from IONVs, another newer approach to induce ferroptosis in tumour cells is through oncolytic virus (OVs). One such oncolytic virus is the Newcastle Disease Virus (NDV), which can only multiply in cancer cells through the p53-SLC7A11-GPX4 pathway that leads to elevated levels of lipid peroxide and intracellular reactive oxygen species leading to the induction of ferroptosis that induce ferritinophagy.

Vγ9Vδ2 T-cells are potent inhibitors of SARS-CoV-2 replication and represent effector phenotypes in COVID-19 patients.

Vγ9Vδ2 T-cells play a key role in the innate immune response to viral infections through butyrophilin (BTN)-3A. Here, we reported that blood Vγ9Vδ2 T-cells decreased in clinically mild COVID-19 compared to healthy volunteers (HV), and was maintained up to 28-days and in the recovery period. Terminally differentiated Vγ9Vδ2 T-cells tend to be enriched on the day of diagnosis, 28-days after and during the recovery period. These cells showed cytotoxic and inflammatory activities following anti-BTN3A activation. BTN3A upregulation and Vγ9Vδ2 T-cell infiltration were observed in a lung biopsy from a fatal SARS-CoV-2 infection. In vitro, SARS-CoV-2 infection increased BTN3A expression in macrophages and lung cells that enhanced the anti-SARS-CoV-2 Vγ9Vδ2 T-cells cytotoxicity and IFNγ and TNFα. Increasing concentrations of anti-BTN3A lead to viral replication inhibition. Altogether, we report that Vγ9Vδ2 T-cells are important in the immune response against SARS-CoV-2 infection and that activation by an anti-BTN3A antibody may enhance their response.

Identification of a risk score model based on tertiary lymphoid structure-related genes for predicting immunotherapy efficacy in non-small cell lung cancer.

BACKGROUND: Tertiary lymphoid structures (TLSs) affect the prognosis and efficacy of immunotherapy in patients with non-small cell lung cancer (NSCLC), but the underlying mechanisms are not well understood. METHODS: TLSs were identified and categorized online from the Cancer Digital Slide Archive (CDSA). Overall survival (OS) and disease-free survival (DFS) were analyzed. GSE111414 and GSE136961 datasets were downloaded from the GEO database. GSVA, GO and KEGG were used to explore the signaling pathways. Immune cell infiltration was analyzed by xCell, ssGSEA and MCP-counter. The analysis of WGCNA, Lasso and multivariate cox regression were conducted to develop a gene risk score model based on the SU2C-MARK cohort. RESULTS: TLS-positive was a protective factor for OS according to multivariate cox regression analysis (p = 0.029). Both the TLS-positive and TLS-mature groups exhibited genes enrichment in immune activation pathways. The TLS-mature group showed more activated dendritic cell infiltration than the TLS-immature group. We screened TLS-related genes using WGCNA. Lasso and multivariate cox regression analysis were used to construct a five-genes (RGS8, RUF4, HLA-DQB2, THEMIS, and TRBV12-5) risk score model, the progression free survival (PFS) and OS of patients in the low-risk group were markedly superior to those in the high-risk group (p < 0.0001; p = 0.0015, respectively). Calibration and ROC curves indicated that the combined model with gene risk score and clinical features could predict the PFS of patients who have received immunotherapy more accurately than a single clinical factor. CONCLUSIONS: Our data suggested a pivotal role of TLSs formation in survival outcome and immunotherapy response of NSCLC patients. Tumors with mature TLS formation showed more activated immune microenvironment. In addition, the model constructed by TLS-related genes could predict the response to immunotherapy and is meaningful for clinical decision-making.

Prognostic model based on B cell marker genes for NSCLC patients under neoadjuvant immunotherapy by integrated analysis of single-cell and bulk RNA-sequencing data.

BACKGROUND: Neoadjuvant immunotherapy has evolved as an effective option to treat non-small cell lung cancer (NSCLC). B cells play essential roles in the immune system as well as cancer progression. However, the repertoire of B cells and its association with clinical outcomes remains unclear in NSCLC patients receiving neoadjuvant immunotherapy. METHODS: Single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing data for LUAD samples were accessed from the TCGA and GEO databases. LUAD-related B cell marker genes were confirmed based on comprehensive analysis of scRNA-seq data. We then constructed the B cell marker gene signature (BCMGS) and validated it. In addition, we evaluated the association of BCGMS with tumor immune microenvironment (TIME) characteristics. Furthermore, we validated the efficacy of BCGMS in a cohort of NSCLC patients receiving neoadjuvant immunotherapy. RESULTS: A BCMGS was constructed based on the TCGA cohort and further validated in three independent GSE cohorts. In addition, the BCMGS was proven to be significantly associated with TIME characteristics. Moreover, a relatively higher risk score indicated poor clinical outcomes and a worse immune response among NSCLC patients receiving neoadjuvant immunotherapy. CONCLUSIONS: We constructed an 18-gene prognostic signature derived from B cell marker genes based on scRNA-seq data, which had the potential to predict the prognosis and immune response of NSCLC patients receiving neoadjuvant immunotherapy.

Identification and validation of an immune-derived multiple programmed cell death index for predicting clinical outcomes, molecular subtyping, and drug sensitivity in lung adenocarcinoma.

OBJECTIVES: Comprehensive cross-interaction of multiple programmed cell death (PCD) patterns in the patients with lung adenocarcinoma (LUAD) have not yet been thoroughly investigated. METHODS: Here, we collected 19 different PCD patterns, including 1911 PCD-related genes, and developed an immune-derived multiple programmed cell death index (MPCDI) based on machine learning methods. RESULTS: Using the median MPCDI scores, we categorized the LUAD patients into two groups: low-MPCDI and high-MPCDI. Our analysis of the TCGA-LUAD training cohort and three external GEO cohorts (GSE37745, GSE30219, and GSE68465) revealed that patients with high-MPCDI experienced a more unfavorable prognosis, whereas those with low-MPCDI had a better prognosis. Furthermore, the results of both univariate and multivariate Cox regression analyses further confirmed that MPCDI serves as a novel independent risk factor. By combining clinical characteristics with the MPCDI, we constructed a nomogram that provides an accurate and reliable quantitative tool for personalized clinical management of LUAD patients. The findings obtained from the analysis of C-index and the decision curve revealed that the nomogram outperformed various clinical variables in terms of net clinical benefit. Encouragingly, the low-MPCDI patients are more sensitive to commonly used chemotherapy drugs, which suggests that MPCDI scores have a guiding role in chemotherapy for LUAD patients. CONCLUSION: Therefore, MPCDI can be used as a novel clinical diagnostic classifier, providing valuable insights into the clinical management and clinical decision-making for LUAD patients.