Deciphering colorectal cancer radioresistance and immune microrenvironment: unraveling the role of EIF5A through single-cell RNA sequencing and machine learning.

Background: Radiotherapy (RT) is a critical component of treatment for locally advanced rectal cancer (LARC), though patient response varies significantly. The variability in treatment outcomes is partly due to the resistance conferred by cancer stem cells (CSCs) and tumor immune microenvironment (TiME). This study investigates the role of EIF5A in radiotherapy response and its impact on the CSCs and TiME. Methods: Predictive models for preoperative radiotherapy (preRT) response were developed using machine learning, identifying EIF5A as a key gene associated with radioresistance. EIF5A expression was analyzed via bulk RNA-seq and single-cell RNA-seq (scRNA-seq). Functional assays and in vivo experiments validated EIF5A's role in radioresistance and TiME modulation. Results: EIF5A was significantly upregulated in radioresistant colorectal cancer (CRC) tissues. EIF5A knockdown in CRC cell lines reduced cell viability, migration, and invasion after radiation, and increased radiation-induced apoptosis. Mechanistically, EIF5A promoted cancer stem cell (CSC) characteristics through the Hedgehog signaling pathway. Analysis of the TiME revealed that the radiation-resistant group had an immune-desert phenotype, characterized by low immune cell infiltration. In vivo experiments showed that EIF5A knockdown led to increased infiltration of CD8+ T cells and M1 macrophages, and decreased M2 macrophages and Tregs following radiation therapy, thereby enhancing the radiotherapy response. Conclusion: EIF5A contributes to CRC radioresistance by promoting CSC traits via the Hedgehog pathway and modulating the TiME to an immune-suppressive state. Targeting EIF5A could enhance radiation sensitivity and improve immune responses, offering a potential therapeutic strategy to optimize radiotherapy outcomes in CRC patients.

Immune-targeted therapy with transarterial chemo(embolization) for unresectable HCC: a systematic review and meta-analysis.

Background: Transarterial chemo(embolization) is preferred for treating unresectable hepatocellular carcinoma (uHCC); however, because of emerging immune-targeted therapies, its efficacy is at stake. This systematic review pioneers to evaluate the clinical efficacy and safety of transarterial chemo(embolization) combined with immune-targeted therapy for uHCC patients. Methods: PubMed, Embase, and Cochrane Library were searched for studies comparing immune-targeted therapy with or without transarterial chemo(embolization) until 31 May 2024. The complete response (CR) rate, objective response rate (ORR), and disease control rate (DCR) were considered to be the primary outcomes calculated for the clinical outcomes of transarterial chemo(embolization) combined with immune-targeted therapy, along with progression-free survival (PFS) and overall survival (OS). The incidence of treatment-related severe adverse events was set as the major measure for the safety outcome. Results: Sixteen studies, encompassing 1,789 patients receiving transarterial chemo(embolization) plus immune-targeted therapy and 1,215 patients receiving immune-targeted therapy alone, were considered eligible. The combination of transarterial chemo(embolization) and immune-targeted therapy demonstrated enhanced outcomes in CR (OR = 2.12, 95% CI = 1.35-3.31), ORR (OR = 2.78, 95% CI = 2.15-3.61), DCR (OR = 2.46, 95% CI = 1.72-3.52), PFS (HR = 0.59, 95% CI = 0.50-0.70), and OS (HR = 0.51, 95% CI = 0.44-0.59), albeit accompanied by a surge in ALT (OR = 2.17, 95% CI = 1.28-3.68) and AST (OR = 2.28, 95% CI = 1.42-3.65). The advantages of additional transarterial chemo(embolization) to immune-targeted therapy were also verified in subgroups of first-line treatment, intervention techniques, with or without extrahepatic metastasis, Child-Pugh grade A or B, and with or without tumor thrombus. Conclusion: The combination of transarterial chemo(embolization) and immune-targeted therapy seems to bolster local control and long-term efficacy in uHCC, albeit at the expense of hepatic complications. Systematic review registration: http://www.crd.york.ac.uk/PROSPERO/, identifier 474669.

Systematic pan-cancer analysis identifies cGAS as an immunological and prognostic biomarker.

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus causes novel coronavirus disease 2019 (COVID-19), which is characterized by pneumonia, cytokine storms, and lymphopenia. Due to immunosuppression, cancer patients may be more susceptible to SARS-CoV-2 and have more serious complications. According to recent research, cyclic GMP-AMP synthase (cGAS) could be a potential SARS-CoV-2 sensor. However, at present, no studies have been conducted on cGAS gene alterations in pan-cancer. This study aimed to discover therapeutic implications for COVID-19-infected tumor patients by performing a comprehensive analysis of cGAS in malignant tumors. Methods: cGAS expression matrices were obtained from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Cancer Cell Line Encyclopedia (CCLE) databases, which were used to evaluate cGAS expression in various tumors, its prognostic value, and its relationship to the immune microenvironment, microsatellite instability (MSI), immune neoantigens, gene mutations, immune checkpoints, MSI, tumor mutational burden (TMB), mismatch repair (MMR) genes, and DNA methyltransferases (DNMT). We also used the cBioPortal, Human Protein Atlas (HPA), and GeneMANIA databases to explore the types of changes, gene networks and immunofluorescence localization, and protein expression of these genes. Results: Compared to normal tissues, cGAS was highly expressed in 13 types of cancer (e.g., lung cancer) and lowly expressed in other cancers (e.g., pancreatic cancer). cGAS expression was associated with prognosis in nine cancers, such as renal clear cell carcinoma (P<0.05). Furthermore, deep deletion was the most common type of cGAS genomic mutation. DNMT, immune infiltration levels, TMB, MSI, MMR genes, neoantigens, and immune checkpoints were all correlated with cGAS expression. Moreover, we used the GSE30589 dataset to investigate the post-SARS-CoV infection changes in cGAS expression in vitro. Finally, mithramycin, MI219, AFP464, aminoflavone, kahalide F, AT13387, doxorubicin, and other drugs increased the sensitivity of cGAS expression. According to the evidence presented above, cGAS may become an important target for cancer therapy. Conclusions: This study discovered that SARS-CoV-2-infected cancer patients might experience changes in their tumor environment as a result of cGAS, making patients with tumors expressing high cGAS more susceptible to COVID-19 and possibly a worsening prognosis. Furthermore, cGAS may be a novel biomarker for diagnosing and treating COVID-19-infected tumor patients.

Corrigendum: The Significance of Transarterial Chemo(embolization) Combined With Tyrosine Kinase Inhibitors and Immune Check Point Inhibitors for Unresectable Hepatocellular Carcinoma in the Era of Systemic Therapy: A Systematic Review.

[This corrects the article DOI: 10.3389/fimmu.2022.913464.].

The Significance of Transarterial Chemo(Embolization) Combined With Tyrosine Kinase Inhibitors and Immune Checkpoint Inhibitors for Unresectable Hepatocellular Carcinoma in the Era of Systemic Therapy: A Systematic Review.

Background and Aims: Regardless of great progress in early detection of hepatocellular carcinoma (HCC), unresectable HCC (uHCC) still accounts for the majority of newly diagnosed HCC with poor prognosis. With the promising results of a double combination of transarterial chemo(embolization) and tyrosine kinase inhibitors (TKIs), and TKIs and immune checkpoint inhibitors (ICIs), a more aggressive strategy, a triple combination of transarterial chemo(embolization), TKIs, and ICIs has been tried in the recent years. Hence, we aimed to conduct a systematic review to verify the safety and efficacy of the triple therapy for uHCC. Methods: PubMed, MedLine, Embase, the Cochrane Library, and Web of Knowledge were used to screen the eligible studies evaluating the clinical efficacy and safety of triple therapy for patients with uHCC up to April 25th 2022, as well as Chinese databases. The endpoints were the complete response (CR), objective response rate (ORR), disease control rate (DCR), conversion rate, progression-free survival (PFS) rate, overall survival (OS) rate, and the incidence of adverse events (AEs). Results: A total of 15 studies were eligible with 741 patients receiving transarterial chemoembolization (TACE) or hepatic arterial infusion chemotherapy (HAIC) combined with TKIs and ICIs. The pooled rate and 95% confidence interval (CI) for CR, ORR, and DCR were 0.124 (0.069-0.190), 0.606 (0.528-0.682), and 0.885 (0.835-0.927). The pooled rates for PFS at 0.5 years and 1 year were 0.781 (0.688-0.862) and 0.387 (0.293-0.486), respectively. The pooled rates for OS at 1, 2, and 3 years were 0.690 (0.585-0.786), 0.212 (0.117-0.324), and 0.056 (0.028-0.091), respectively. In addition, the pooled rate and 95%CI for the conversion surgery was 0.359 (0.153-0.595). The subgroup analysis of control studies showed that triple therapy was superior to TACE+TKIs, TKIs+ICIs, and TKIs in CR, ORR, and DCR, conversion rate; PFS; and OS. No fatal AEs were reported, and the top three most common AEs were elevated ALT, elevated AST, and hypertension, as well as severe AEs (grading ≥3). Conclusion: With the current data, we concluded that the triple therapy of TACE/HAIC, TKIs, and ICIs would provide a clinical benefit for uHCC both in short- and long-term outcomes without increasing severe AEs, but the conclusion needs further validation. Systematic Review Registration: http://www.crd.york.ac.uk/PROSPERO/, Review registry: CRD42022321970.