Tumor Immune Cells Research Articles

Expression, prognostic value and potential immunotherapeutic target of COL1A1 in colon cancer.

This study aimed to investigate the link between COL1A1 production and colorectal carcinoma and assess the value of prognosis and immunotherapy. For this purpose, the transcriptional level of COL1A1 was analyzed. The clinicopathological information and gene expression profile were analyzed to reveal the link between COL1A1 and clinicopathological characteristics. For bioinformatics examination, GSEA and GSVA were utilized. Correlation analysis was implemented to study the causal relationship between COL1A1 and immune checkpoint molecules and inflammation immune cell infiltration. Results showed that in colorectal cancer, COL1A1 was highly expressed and linked with a few clinicopathological characteristics, inflammation and immunological response, tumor immune cell infiltration, and immune checkpoint markers. COL1A1 might likely indicate a bad prognosis and serve as a target of immunotherapy for colon cancer.

Multidimensional Analysis of PANoptosis-Related Molecule CASP8: Prognostic Significance, Immune Microenvironment Effect, and Therapeutic Implications in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) presents significant challenges in diagnosis and treatment. Understanding the role of PANoptosis-related molecules in HCC is crucial for advancing therapeutic strategies. We conducted a comprehensive analysis using public data from the Cancer Genome Atlas, Human Protein Atlas, Tumor Immune Single Cell Hub, and STRING databases. Techniques included Kaplan-Meier survival curves, Cox regression, LASSO analysis, and various computational methods for understanding the tumor microenvironment. We also employed ClueGO, gene set enrichment analysis, and other algorithms for biological enrichment analysis. CASP8 emerged as a significant molecule in HCC, correlated with poor survival outcomes. Its expression was predominant in the nucleoplasm and cytosol and varied across different cancer types. Biological enrichment analysis revealed CASP8's association with critical cellular activities and immune responses. In the tumor microenvironment, CASP8 showed correlations with various immune cell types. A nomogram plot was developed for better clinical prognostication. Mutation analysis indicated a higher frequency of TP53 mutations in patients with elevated CASP8 expression. In addition, CASP8 was found to regulate YEATS2 in HCC, highlighting a potential pathway in tumor progression. Our study underscores the multifaceted role of CASP8 in HCC, emphasizing its prognostic and therapeutic significance. The regulatory relationship between CASP8 and YEATS2 opens new avenues for understanding HCC pathogenesis and treatment strategies.

Single-cell deconvolution reveals high lineage- and location-dependent heterogeneity in mesenchymal multivisceral stage 4 colorectal cancer.

Metastasized colorectal cancer (CRC) is associated with a poor prognosis and rapid disease progression. Besides hepatic metastasis, peritoneal carcinomatosis is the major cause of death in Union for International Cancer Control (UICC) stage IV CRC patients. Insights into differential site-specific reconstitution of tumor cells and the corresponding tumor microenvironment are still missing. Here, we analyzed the transcriptome of single cells derived from murine multivisceral CRC and delineated the intermetastatic cellular heterogeneity regarding tumor epithelium, stroma, and immune cells. Interestingly, we found an intercellular site-specific network of cancer-associated fibroblasts and tumor epithelium during peritoneal metastasis as well as an autologous feed-forward loop in cancer stem cells. We furthermore deciphered a metastatic dysfunctional adaptive immunity by a loss of B cell-dependent antigen presentation and consecutive effector T cell exhaustion. Furthermore, we demonstrated major similarities of this murine metastatic CRC model with human disease and - based on the results of our analysis - provided an auspicious site-specific immunomodulatory treatment approach for stage IV CRC by intraperitoneal checkpoint inhibition.

Copper metabolism-related risk score identifies hepatocellular carcinoma subtypes and SLC27A5 as a potential regulator of cuproptosis.

Dysregulated copper metabolism has been noticed in many types of cancer including hepatocellular carcinoma (HCC); however, a comprehensive understanding about this dysregulation still remains unclear in HCC. A set of bioinformatic tools was integrated to analyze the expression and prognostic significance of copper metabolism-related genes. A related risk score, termed as CMscore, was developed via univariate Cox regression, least absolute shrinkage and selection operator (LASSO) Cox regression and multivariate Cox regression. Pathway enrichment analyses and tumor immune cell infiltration were further investigated in CMscore stratified HCC patients. Weighted correlation network analysis (WGCNA) was used to identify potential regulator of cuproptosis. Copper metabolism was dysregulated in HCC. HCC patients in the high-CMscore group showed a significantly lower overall survival (OS) and enriched in most cancer-related pathways. Besides, HCC patients with high CMscore had higher expression of pro-tumor immune infiltrates and immune checkpoints. Moreover, cancer patients with high CMscore from two large cohorts exhibited significantly prolonged survival time after immunotherapy. WGCNA and subsequently correlation analysis revealed that SLC27A5 might be a potential regulator of cuproptosis in HCC. In vitro experiments revealed that SLC27A5 inhibited cell proliferation and migration of HCC cells and could upregulate FDX1, the key regulator of cuproptosis. The CMscore is helpful in clustering HCC patients with distinct prognosis, gene mutation signatures, and sensitivity to immunotherapy. SLC27A5 might serve as a potential target in the induction of cuproptosis in HCC.

Comprehensive analysis of disulfidptosis-related lncRNA features for prognosis and immune landscape prediction in colorectal cancer.

Disulfidptosis is a novel mechanism underlying actin-cytoskeleton-associated cell death, but its function in colorectal cancer (CRC) is still elusive. In this study, we investigated the potential role of Disulfidptosis-Related Long Non-Coding RNAs (DRLs) as prognostic indicators in CRC. Through transcriptome data from TCGA CRC cases, we identified 44 prognosis-correlated DRLs by Univariate Cox Regression Analysis and observed a differential expression pattern of these DRLs between CRC and normal tissues. Consensus clustering analysis based on DRL expression led to subgroup classification of CRC patients with distinct molecular fingerprints, accompanied by a superior survival outcome in cluster 2. We are encouraged to develop a score model incorporating 12 key DRLs to predict patient outcomes. Notably, this model displayed more reliable accuracy than other predictive indicators since DRLs are intimately related to tumor immune cell infiltration, suggesting a considerable potential of our DRL-score model for tumor therapy. Our data offered a valuable insight into the prognostic significance of DRLs in CRC and broke a new avenue for tumor prognosis prediction.

Construction of a prognostic model for lung adenocarcinoma based on m6A/m5C/m1A genes.

Developing a prognostic model for lung adenocarcinoma (LUAD) that utilizes m6A/m5C/m1A genes holds immense importance in providing precise prognosis predictions for individuals. This study mined m6A/m5C/m1A-related differential genes in LUAD based on public databases, identified LUAD tumor subtypes based on these genes, and further built a risk prognostic model grounded in differential genes between subtypes. The immune status between high- and low-risk groups was investigated, and the distribution of feature genes in tumor immune cells was analyzed using single-cell analysis. Based on the expression levels of feature genes, a projection of chemotherapeutic and targeted drugs was made for individuals identified as high-risk. Ultimately, cell experiments were further verified. The 6-gene risk prognosis model based on differential genes between tumor subtypes had good predictive performance. Individuals classified as low-risk exhibited a higher (P < 0.05) abundance of infiltrating immune cells. Feature genes were mainly distributed in tumor immune cells like CD4+T cells, CD8+T cells, and regulatory T cells. Four drugs with relatively low IC50 values were found in the high-risk group: Elesclomol, Pyrimethamine, Saracatinib, and Temsirolimus. In addition, four drugs with significant positive correlation (P < 0.001) between IC50 values and feature gene expression were found, including Alectinib, Estramustine, Brigatinib, and Elesclomol. The low expression of key gene NTSR1 reduced the IC50 value of irinotecan. Based on the m6A/m5C/m1A-related genes in LUAD, LUAD patients were divided into 2 subtypes, and a m6A/m5C/m1A-related LUAD prognostic model was constructed to provide a reference for the prognosis prediction of LUAD.

Experimental validation and pan-cancer analysis identified COL10A1 as a novel oncogene and potential therapeutic target in prostate cancer.

Type X collagen (COL10) is a homologous trimeric non-fibrillar collagen found in the extracellular matrix of human tissues, and it exhibits a distinctive white appearance. Type X collagen α1 chain (COL10A1) is a specific cleaved fragment of type X collagen. However, the expression, prognostic significance, clinicopathological attributes and immune-related associations of COL10A1 in prostate cancer as well as in pan-cancer contexts remain poorly understood. Using bioinformatic analysis of data from the most recent databases (TCGA, GTEx and GEO databases), we have extensively elucidated the role played by COL10A1 in terms of its expression patterns, prognostic implications, and immune efficacy across a pan-cancer spectrum. Subsequently, the biological functions of COL10A1 in prostate cancer were elucidated by experimental validation. Our findings have confirmed that COL10A1 was highly expressed in most cancers and was associated with poorer prognosis in cancer patients. Immune correlation analysis of COL10A1 in various cancers showed its significant correlation with Tumor mutational burden (TMB), microsatellite instability (MSI) and immune cell infiltration. In addition, knockdown of COL10A1 in prostate cancer resulted in a substantial reduction in the proliferation, migration, and invasive potential of prostate cancer cells. Our pan-cancer analysis of COL10A1 gene provided novel insights into its pivotal role in cancer initiation, progression, and therapeutic implications, underscoring its potential significance in prognosis and immunotherapeutic interventions for cancer, particularly prostate cancer.

Three-dimensional cell models for studying tumor–immune interactions and testing immunotherapeutic drugs

One of the most promising approaches to cancer treatment is immunotherapy. Suppression of immune checkpoints in tumor tissue (anti-CTLA4, anti-PD1) using monoclonal antibodies has increased the overall survival of patients with some forms of skin melanoma and lung cancer. However, the percentage of patients responding to treatment varies from 20% to 40% depending on the type of cancer and the expression of target molecules by the tumor. The main source of failure of immunotherapy is the tumor microenvironment, which affects both tumor cells and immune cells, causing them to adapt to immunotherapeutic drugs. It is known that the architecture and cellular composition of the microenvironment act on various tumor parameters, promoting the recruitment of immunosuppressive cells into the tumor tissue, as well as the expression of checkpoint inhibitors, such as PD-L1, by tumor cells. Therefore, the complex composition of the tumor microenvironment must be taken into account when searching for new therapies and stratifying patients who may respond to immunotherapy. Therefore, in immunooncological studies, it is necessary to use three-dimensional cellular models that more fully reflect the architecture and cellular composition of the tumor. In this review, we evaluate three-dimensional cell models as tools for research in the field of immuno-oncology, as well as for personalized treatment selection, the search for new targets, and the optimization of existing cancer immunotherapies.

Identification and validation of prognostic and tumor microenvironment characteristics of necroptosis index and BIRC3 in clear cell renal cell carcinoma.

Necroptosis is a form of programmed cell death; it has an important role in tumorigenesis and metastasis. However, details of the regulation and function of necroptosis in clear cell renal cell carcinoma (ccRCC) remain unclear. It is necessary to explore the significance of necroptosis in ccRCC. Necroptosis-related clusters were discerned through the application of Consensus Clustering. Based on the TCGA and GEO databases, we identified prognostic necroptosis-related genes (NRGs) with univariate COX regression analysis. The necroptosis-related model was constructed through the utilization of LASSO regression analysis, and the immune properties, tumor mutation burden, and immunotherapy characteristics of the model were assessed using multiple algorithms and datasets. Furthermore, we conducted comprehensive GO, KEGG, and GSVA analyses to probe into the functional aspects of biological pathways. To explore the expression and of hub gene (BIRC3) in different ccRCC cell types and cell lines, single-cell sequencing data was analysed and we performed Quantitative Real-time PCR to detect the expression of BIRC3 in ccRCC cell lines. Function of BIRC3 in ccRCC was assessed through Cell Counting Kit-8 (CCK8) assay (for proliferation), transwell and wound healing assays (for migration and invasion). Distinct necroptosis-related clusters exhibiting varying prognostic implications, and enrichment pathways were identified in ccRCC. A robust necroptosis-related model formulated based on the expression of six prognostic NRGs, presented substantial predictive capabilities of overall survival and was shown to be related with patients' immune profiles, tumor mutation burden, and response to immunotherapy. Notably, the hub gene BIRC3 was markedly upregulated in both ccRCC tissues and cell lines, and showed significant correlations with immunosuppressive cells, immune checkpoints, and oncogenic pathways. Downregulation of BIRC3 demonstrated a negative regulatory effect on ccRCC cell proliferation migration and invasion. The necroptosis-related model assumed a pivotal role in determining the prognosis, tumor mutation burden, immunotherapy response, and immune cell infiltration characteristics among ccRCC patients. BIRC3 exhibited significant correlations with the immunosuppressive microenvironment, which highlighted its potential for informing the design of innovative immunotherapies for ccRCC patients.

Potential prognostic value of ITPR1 in thyroid carcinoma: An integrated analysis

PurposeInositol 1,4,5-trisphosphate receptor type1 (ITPR1) is reported to play an important role in malignancy. We aim to explore the potential role of ITPR1 in thyroid carcinoma (THCA). MethodWe collected THCA tissues and adjacent non-cancerous tissues as well as clinical information from 99 patients with THCA (69 females and 30 males). Quantitative real-time quantitative polymerase chain reactions and immunohistochemical were performed to investigate ITPR1 messenger RNA (mRNA) and protein expression between THCA tissues and adjacent non-cancerous tissues, and the relationship between ITPR1 mRNA expression and clinical parameters were analyzed. Bioinformatics techniques were used to analyze ITPR1 in THCA from publicly available datasets including The Cancer Genome Atlas, Gene Expression Omnibus dataset, LinkedOmics, Kaplan Meier plotter, TNMplot, muTarget, TIMER, TIMER2, TISIDB, Gene Expression Profiling Interactive Analysis and Search Tool for the Retrieval of Interacting Genes. ResultsITPR1 mRNA and protein expression was down-regulated in THCA tissues. Low ITPR1 mRNA expression was associated with larger tumor size, lymph node metastasis, advanced stages, and BRAF mutation of TCHA patients. Moreover, the high mRNA expression of ITPR1 is unfavorable in patients with THCA. ITPR1 mRNA expression was positively associated with thyroid iodide-handling genes including TPO, PAX8, TG, TSHR and SLC5A5. And ITPR1 was an autophagy-gene in THCA and participated in autophagy-associated pathways. Additionally, ITPR1 may regulate proliferation capacity in THCA by interacting with microRNAs-144/221/222/101/500/501 and involve in drug resistance of cancer treatment via OCT1 family. ITPR1 was potentially correlated with infiltrating levels of tumor-immune cells and CXCL1/2/3/5/8/9/10/11/13/14/16/17. ConclusionThrough clinical data investigation and bioinformatic analysis, this work showed the potential role of ITPR1in carcinogenesis and diagnostic in THCA patients.

Exploratory analyses of treatment subgroup interaction by PD-L1 status and according to PD-L1 expression in the JAVELIN Bladder 100 trial.

Post hoc analysis of the JAVELIN Bladder 100 trial of avelumab maintenance in locally advanced/metastatic urothelial carcinoma (la/mUC) to determine the interaction by programmed death ligand 1 (PD-L1) status for overall survival (OS), and additional analyses of survival per a different PD-L1 expression cutoff of ≥ 1% in tumor cells or immune cells (TC/IC). JAVELIN Bladder 100 data were used for the analysis of the interaction by PD-L1 status (per cutoff used in the trial) for OS and, additionally, OS and progression-free survival (PFS) analyses per a different ≥ 1% TC/IC PD-L1 expression cutoff (Ventana SP263 assay). No significant interaction between treatment and PD-L1 status was observed for OS. Clinically meaningful and robust survival data were observed in favor of avelumab using the different ≥ 1% TC/IC PD-L1 expression cutoff. These results demonstrate the benefit of avelumab maintenance in la/mUC regardless of PD-L1 expression, consistent with approved labels.

Programmable DNA Hydrogel Assisting Microcrystal Formulations for Sustained Locoregional Drug Delivery in Surgical Residual Tumor Lesions and Lymph Node Metastasis.

Surgical residual tumor lesions (R1 resection of surgical procedures (e.g., liver cancer infiltrating the diaphragm, surgical residual breast cancer, postoperative residual ovarian cancer) or boundary residual after ablation) and lymph node metastasis that cannot be surgically resected (retroperitoneal lymph nodes) significantly affect postoperative survival of tumor patients. This clinical conundrum poses three challenges for local drug delivery systems: stable and continuous delivery, good biocompatibility, and the ability to package new targeted drugs that can synergize with other treatments. Here, a drug-laden hydrogel generated from pure DNA strands and highly programmable in adjusting its mesh size is reported. Meanwhile, the DNA hydrogel can assist the microcrystallization of novel radiosensitizing drugs, ataxia telangiectasia and rad3-related protein (ATR) inhibitor (Elimusertib), further facilitating its long-term release. When applied to the tumor site, the hydrogel system demonstrates significant antitumor activity, minimized systemic toxicity, and has a modulatory effect on the tumor-immune cell interface. This drug-loaded DNA-hydrogel platform represents a novel modality for adjuvant therapy in patients with surgical residual tumor lesions and lymph node metastasis.

Predictive role of E2F6 in cancer prognosis and responses of immunotherapy

BackgroundE2F6 is a member of the E2F transcription factor family. Numerous studies have demonstrated that E2F6 is critical to cancer development and progression, but its role in cancer immunotherapy remains unclear. MethodsGenotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases were used to obtain RNA-seq data for cancer and normal tissues, and we utilized the cBioPortal to analyze E2F6 genomic alterations in pan-cancer. The protein localization of E2F6 was obtained using the Human Protein Atlas (HPA), and the upregulation of E2F6 expression in clinical glioblastoma multiforme (GBM) tissues was detected by Western blot analysis. The ComPPI website was used to analyze the protein interaction information of E2F6. To evaluate the role of E2F6 in pan-cancer prognosis, we used univariate Cox regression and Kaplan-Meier methods, and gene set enrichment analysis (GSEA) was utilized to identify markers associated with E2F6 expression in tumors. TIMER 2.0 was used to study E2F6-related immune cell infiltration in tumor tissues, and the correlation of E2F6 with immunotherapy biomarkers was investigated using Spearman correlation analysis. The role of E2F6 in the cell cycle was analyzed by flow cytometry, and the Cell Counting Kit-8 (CCK-8) and colony formation assays were utilized to determine the proliferative ability of cells. ResultsIn most tumor types, E2F6 was highly expressed and was a good predictor of prognosis. E2F6 was significantly related to markers of immune activation, tumor immune cell infiltration, and immune regulators. Furthermore, E2F6 knockdown significantly attenuated the proliferative ability of glioma cells. Finally, E2F6 effectively predicted anti-programmed cell death 1 (PD1) treatment response. ConclusionE2F6 is an effective biomarker that predicts the prognosis of cancer patients treated with anti-immune checkpoint therapy.

Prognostic Implications of LRP1B and Its Relationship with the Tumor-Infiltrating Immune Cells in Gastric Cancer.

Recent studies have shown that low-density lipoprotein receptor-related protein 1b (LRP1B), as a potential tumor suppressor, is implicated in the response to immunotherapy. The frequency of LRP1B mutation gene is high in many cancers, but its role in gastric cancer (GC) has not been determined. The prognostic value of LRP1B mutation in a cohort containing 100 patients having received radical gastrectomy for stage II-III GC was explored. By analyzing the data of LRP1B mRNA, the risk score of differentially expressed genes (DEGs) between LRP1B mutation-type and wild-type was constructed based on the TCGA-STAD cohort. The infiltration of tumor immune cells was evaluated by the CYBERSORT algorithm and verified by immunohistochemistry. LRP1B gene mutation was an independent risk factor for disease-free survival (DFS) in GC patients (HR = 2.57, 95% CI: 1.28-5.14, p = 0.008). The Kaplan-Meier curve demonstrated a shorter survival time in high-risk patients stratified according to risk score (p < 0.0001). CYBERSORT analysis showed that the DEGs were mainly concentrated in CD4+ T cells and macrophages. TIMER analysis suggested that LRP1B expression was associated with the infiltration of CD4+ T cells and macrophages. Immunohistochemistry demonstrated that LRP1B was expressed in the tumor cells (TCs) and immune cells in 16/89 and 26/89 of the cohort, respectively. LRP1B-positive TCs were associated with higher levels of CD4+ T cells, CD8+ T cells, and CD86/CD163 (p < 0.05). Multivariate analysis showed that LRP1B-positive TCs represented an independent protective factor of DFS in GC patients (HR = 0.43, 95% CI: 0.10-0.93, p = 0.042). LRP1B has a high prognostic value in GC. LRP1B may stimulate tumor immune cell infiltration to provide GC patients with survival benefits.

Immune Cells in the Tumor Microenvironment of Soft Tissue Sarcomas.

Soft tissue sarcomas (STSs) are a rare heterogeneous group of malignant neoplasms characterized by their aggressive course and poor response to treatment. This determines the relevance of research aimed at studying the pathogenesis of STSs. By now, it is known that STSs is characterized by complex relationships between the tumor cells and immune cells of the microenvironment. Dynamic interactions between tumor cells and components of the microenvironment enhance adaptation to changing environmental conditions, which provides the high aggressive potential of STSs and resistance to antitumor therapy. Today, active research is being conducted to find effective antitumor drugs and to evaluate the possibility of using therapy with immune cells of STS. The difficulty in assessing the efficacy of new antitumor options is primarily due to the high heterogeneity of this group of malignant neoplasms. Studying the role of immune cells in the microenvironment in the progression STSs and resistance to antitumor therapies will provide the discovery of new biomarkers of the disease and the prediction of response to immunotherapy. In addition, it will help to initially divide patients into subgroups of good and poor response to immunotherapy, thus avoiding wasting precious time in selecting the appropriate antitumor agent.

LAG3 is an independent prognostic biomarker and potential target for immune checkpoint inhibitors in malignant pleural mesothelioma: a retrospective study

BackgroundLymphocyte-activation gene 3 (LAG3) is an immune checkpoint receptor; novel LAG3 immune checkpoint inhibitors (ICIs) exhibit therapeutic activity in melanoma. The role of LAG3and ICIs of LAG3 are unknown in malignant pleural mesothelioma (MPM). This study aimed to uncover the prognostic landscape of LAG3 in multiple cancers and investigate the potential of using LAG3 as an ICIs target in patients with MPM.MethodsWe used The Cancer Genome Atlas (TCGA) cohort for assessing mRNA expression and our cohort for immunohistochemical expression. TCGA cohort were analyzed using the Wilcoxon rank-sum test to compare mRNA expression between normal and tumor tissues in multiple cancers. We used 86 MPM cases from TCGA and 38 MPM cases from our cohort to analyze the expression of LAG3 in tumor-infiltrating lymphocytes. The mean LAG3 mRNA expression was set as the cut-off and samples were classified as positive/negative for immunohistochemical expression. Overall survival (OS) of patients with MPM was determined using the Kaplan–Meier method based on LAG3 mRNA and immunohistochemical expression. OS analysis was performed using the multivariate Cox proportional hazards model. The correlation of LAG3 expression and mRNA expression of tumor immune infiltration cells (TIICs) gene markers were estimated using Spearman correlation. To identify factors affecting the correlation of LAG3 mRNA expression, a multivariate linear regression model was performed.ResultsLAG3 mRNA was associated with prognosis in multiple cancers. Elevated LAG3 mRNA expression was correlated with a better prognosis in MPM. LAG3 expression was detected immunohistochemically in the membrane of infiltrating lymphocytes in MPM. LAG3 immunohistochemical expression was correlated with a better prognosis in MPM. The multivariate Cox proportional hazards model revealed that elevated LAG3 immunohistochemical expression indicated a better prognosis. In addition, LAG3 mRNA expression was correlated with the expression of various gene markers of TIICs, the most relevant to programmed cell death 1 (PD-1) with the multivariate linear regression model in MPM.ConclusionsLAG3 expression was correlated with prognosis in multiple cancers, particularly MPM; LAG3 is an independent prognostic biomarker of MPM. LAG3 regulates cancer immunity and is a potential target for ICIs therapy. PD-1 and LAG3 inhibitors may contribute to a better prognosis in MPM.Trial registrationThis study was registered with UMIN000049240 (registration day: August 19, 2022) and approved by the Institutional Review Board (approval date: August 22, 2022; approval number: 2022–0048) at Tokyo Women’s Medical University.

Advanced Generation Therapeutics: Biomimetic Nanodelivery System for Tumor Immunotherapy.

Tumor immunotherapy is a safe and effective strategy for precision medicine. However, immunotherapy for most cancer cases still ends in failure, with the root causes of the immunosuppressive and extraordinary heterogeneity of the solid tumors microenvironment. The emerging biomimetic nanodelivery system provides a promising tactic to improve the immunotherapy effect while reducing the adverse reactions on nontarget cells. Herein, we summarize the relationship between tumor occurrence and tumor immune microenvironment, mechanism of tumor immune escape, immunotherapy classification (including adoptive cellular therapy, cytokines, cancer vaccines, and immune checkpoint inhibitors) and recommend target cells for immunotherapy first, and then emphatically introduce the recent advances and applications of the latest biomimetic nanodelivery systems (e.g., immune cells, erythrocytes, tumor cells, platelets, bacteria) in tumor immunotherapy. Meanwhile, we separately summarize the application of tumor vaccines. Finally, the predictable challenges and perspectives in a forward exploration of biomimetic nanodelivery systems for tumor immunotherapy are also discussed.

ALDOB/KAT2A interactions epigenetically modulate TGF-β expression and T cell functions in hepatocellular carcinogenesis.

Crosstalk between tumor cells and immune cells enables tumor cells to escape immune surveillance and dictate responses to immunotherapy. Previous studies have identified that downregulation of the glycolytic enzyme fructose-1,6-bisphosphate aldolase B (ALDOB) in tumor cells orchestrated metabolic programming to favor hepatocellular carcinogenesis (HCC). However, it remains elusive whether and how ALDOB expression in tumor cells affects the tumor microenvironment in HCC. We found that ALDOB downregulation was negatively correlated with CD8+ T cell infiltration in human HCC tumor tissues but in a state of exhaustion. Similar observations were made in mice with liver-specific ALDOB knockout or in subcutaneous tumor models with ALDOB knockdown. Moreover, ALDOB deficiency in tumor cells upregulates TGF-β expression, thereby increasing the number of Treg cells and impairing the activity of CD8+ T cells. Consistently, a combination of low ALDOB and high TGF-β expression exhibited the worst overall survival for HCC patients. More importantly, the simultaneous blocking of TGF-β and PD-1 with antibodies additively inhibited tumorigenesis induced by ALDOB deficiency in mice. Further mechanistic experiments demonstrated that ALDOB enters the nucleus and interacts with lysine acetyltransferase 2A (KAT2A), leading to inhibition of H3K9 acetylation and thereby suppressing TGFB1 transcription. Consistently, inhibition of KAT2A activity by small molecule inhibitors suppressed TGF-β and HCC. Our study has revealed a novel mechanism by which a metabolic enzyme in tumor cells epigenetically modulates TGF-β signaling, thereby enabling cancer cells to evade immune surveillance and affect their response to immunotherapy.

Identification and validation of a T cell marker gene-based signature to predict prognosis and immunotherapy response in gastric cancer

Although the role of T cells in tumor immunity and modulation of the tumor microenvironment (TME) has been extensively studied, their precise involvement in gastric adenocarcinoma remains inadequately explored. In this work, we analyzed the single-cell RNA sequencing data set in GSE183904 and identified 322 T cell marker genes using the “FindAllMarkers” method of the R package “Seurat”. STAD patients in the TCGA database were divided into high-risk and low-risk categories based on risk scores. The five-gene prediction signature based on T cell marker genes can predict the prognosis of gastric cancer patients with high accuracy. In the training cohort, the areas under the receiver operating characteristic (ROC) curve were 0.667, 0.73, and 0.818 at 1, 3, and 5 years. External validation of the predictive signature was also performed using multiple clinical subgroups and GEO cohorts. To help with practical application, a diagnostic model was created that shows values of 0.732, 0.752, and 0.816 for the relevant areas under the ROC curve at 1, 3, and 5 years. The T cell marker genes identified in this study may serve as potential therapeutic targets, and the developed predictive signatures and nomograms may aid in the clinical management of gastric cancer.

Tumor-immune cell interaction and senescence-associated molecules in colorectal carcinoma

Cellular senescence permanently arrests the cell cycle of premalignant cells following protumorigenic stimuli, counteracting tumor progression. Senescence induction leads to phenotypic and metabolic changes and alters the interaction with the cells' microenvironment. This mediates tumor immunosurveillance but bears promalignant potential and may contribute to disease progression. Our study aims to investigate the prognostic potential of senescence markers in colorectal carcinoma (CRC) and to understand the interaction of senescent tumor cells and immune cells. Immunohistochemical markers were studied on atissue microarray (TMA) containing tumor tissue of n = 598 CRC patients and were evaluated using digital image analysis. Results were correlated with disease-specific survival (DSS) and progression-free survival (PFS). Consecutive TMA sections were stained for senescence markers and immune cell markers to analyze the spatial relation of those cell populations. Senescence was induced in CRC cell lines in vitro and co-cultures with various immune cell lines were established to study the interactions. Expression of different senescent-associated markers is associated with increased or decreased DSS and PFS. Close proximity of p21+ senescent tumor cells and CD8+ immune cells correlates with increased DSS and PFS. In vitro, senescent cells were dose-dependently eliminated by immune cells, which is facilitated via direct cell-cell contact and induction of apoptosis. Depicting the initiation of this important anti-tumor mechanism, markers of cellular senescence are of significant prognostic relevance in CRC. Moreover, our results show the pleiotropic effect of senescence in vivo. Absence as well as exceeding expression of senescence markers are associated with anegative prognosis in CRC. The impact of cellular senescence depends on the tumor microenvironment and the immunosurveillance of senescent cells. Proximity analyses of senescent cells and tumor-infiltrating immune cells have significant prognostic relevance and reflect this.