Immunotherapy Of Colon Cancer Research Articles

Immunotherapy in Stage III-IV Colon Cancer: A Propensity Score-Matched Analysis of the National Cancer Database.

Immunotherapy for the systemic treatment of cancer offers new treatment possibilities for advanced malignancies. Despite promising initial results, evidence on efficacy of immunotherapy for colon cancer is lacking. Thus, we aimed to assess short-term and long-term outcomes of immunotherapy in patients with advanced colon cancer. A US National Cancer Database was searched for patients with stage III-IV colonic adenocarcinoma between 2010 and 2019. Propensity score matching was used to classify the cohort into 2 groups: patients who received immunotherapy and controls. Main outcome measures were primary outcome was overall survival (OS). A total of 23,778 patients with stage III-IV colonic adenocarcinoma were treated with immunotherapy during the study period compared to 114,753 controls. Immunotherapy treated patients were younger (median age 61 vs. 67 y; P <0.001), more often male (57.3% vs. 50.7%, P <0.001), had more private insurance (44.1% vs. 33.7%; P <0.001), had more left-sided tumors (49.5% vs. 39.1%; P <0.001) and liver metastasis (80.2% vs. 61.7%; P <0.001) than controls. Immunotherapy patients received more standard chemotherapy (49.8% vs. 41.6%; P <0.001). After propensity-score matching, mean OS was significantly shorter in the immunotherapy group compared with controls (34.7 vs. 36.2 mo; P =0.008). Cox regression analysis demonstrated that immunotherapy was associated with increased risk for mortality (HR: 1.1; 95% CI: 1.02-1.18; P =0.005). Patients who received immunotherapy had lower 90-day mortality rates compared with controls (2.3% vs. 3.6%; P =0.004), but the groups had equivalent 30-day mortality rates (0.7% vs. 0.8%; P =0.76). Immunotherapy showed no improvement in OS in patients with stage III-IV colon cancer.

Cuproptosis in microsatellite stable colon cancer cells affects the cytotoxicity of CD8+T through the WNT signaling pathway

The microsatellite stable (MSS) colon cancer (CC) has long been considered resistant to immunotherapy. Cuproptosis, as a novel form of cell death, may interact with tumor immunity. This project focused on the impact of cuproptosis on the cytotoxicity of CD8+T in MSS CC, aiming to provide effective clues for improving the treatment strategy of MSS CC. The study developed an MSS CC cuproptosis model using 50 nM elesclomol and 1 μM CuCl2. Cuproptotic SW480 cells were directly co-cultured with CD8+ T cells. Cuproptosis levels were assessed via intracellular copper ion detection, Western blot, and confocal laser scanning microscopy. CCK-8, Hochest/PI staining, CFSE cell proliferation assay, LDH cytotoxicity detection, and ELISA were used to evaluate CD8+ T cell immune activity and cytotoxicity. Transcriptome sequencing and bioinformatics analysis identified regulated signals in cuproptotic SW480 cells. A rescue experiment utilized a WNT pathway activator (BML-284). PD-L1 expression in cells/membranes was analyzed using qRT-PCR, Western blot, and flow cytometry. NSG mice were immunoreconstituted, and the effects of cuproptosis on immune infiltration and cancer progression in MSS CC mice were assessed using ELISA and immunohistochemistry (IHC). Treatment with 50 nM elesclomol and 1 μM CuCl2 significantly increased cuproptosis in SW480 cells. Co-culture with CD8+ T cells enhanced their cytotoxicity. Sequencing revealed cuproptosis-mediated modulation of immune and inflammatory pathways, including WNT signaling. Rescue experiments showed downregulation of WNT signaling in cuproptotic SW480 cells. Indirectly, CD8+ T cell immune function was enhanced by reducing PD-L1 expression. In mice, cuproptosis resulted in increased infiltration of CD8+ T cells in tumor tissue, leading to delayed cancer progression compared to the control group. Cuproptosis in MSS CC cells enhances the cytotoxicity of CD8+ T cells, which may be achieved through downregulation of the WNT signaling pathway and decreased expression of PD-L1. In the future, drugs that can induce cuproptosis may be a promising approach to improve MSS CC immunotherapy.

Microbiota-induced S100A11-RAGE axis underlies immune evasion in right-sided colon adenomas and is a therapeutic target to boost anti-PD1 efficacy

BackgroundTumourigenesis in right-sided and left-sided colons demonstrated distinct features.ObjectiveWe aimed to characterise the differences between the left-sided and right-sided adenomas (ADs) representing the early stage of colonic tumourigenesis.DesignSingle-cell and spatial...

Mucosal-associated invariant T cells modulate innate immune cells and inhibit colon cancer growth.

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that can be activated by microbial antigens and cytokines and are abundant in mucosal tissues including the colon. MAIT cells have cytotoxic and pro-inflammatory functions and have potentials for use as adoptive cell therapy. However, studies into their anti-cancer activity, including their role in colon cancer, are limited. Using an animal model of colon cancer, we showed that peritumoral injection of invivo-expanded MAIT cells into RAG1-/- mice with MC38-derived tumours inhibits tumour growth compared to control. Multiplex cytokine analyses showed that tumours from the MAIT cell-treated group have higher expression of markers for eosinophil-activating cytokines, suggesting a potential association between eosinophil recruitment and tumour inhibition. In a human peripheral leukocyte co-culture model, we showed that leukocytes stimulated with MAIT ligand showed an increase in eotaxin-1 production and activation of eosinophils, associated with increased cancer cell killing. In conclusion, we showed that MAIT cells have a protective role in a murine colon cancer model, associated with modulation of the immune response to cancer, potentially involving eosinophil-associated mechanisms. Our results highlight the potential of MAIT cells for non-donor restricted colon cancer immunotherapy.

Identification and validation of endoplasmic reticulum stress-related genes that enhance immunotherapy in colon cancer.

Endoplasmic reticulum stress (ERS)-related genes are related to tumor growth, metastasis, and immunotherapy response. In this paper, we tried to identify ERS-related genes related to immunotherapy in colon cancer. ERS-related genes were downloaded from the Molecular Signatures Database (MSigDB) and GeneCards websites. Normal and tumor samples of the colon were obtained from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression Project (GTEx), and Gene Expression Omnibus (GEO) databases. A risk model based on gene coefficients was constructed by using the least absolute shrinkage and selection operator (LASSO) regression. The inherent biological process differences between risk groups were explored by Gene Ontology (GO) and gene set enrichment analysis (GSEA). ESTIMATE and single-sample GSEA (ssGSEA) algorithms were used to analyze the correlation between tumor microenvironment (TME) and immune checkpoint and risk score. The semi-inhibitory concentration (IC50) values of chemotherapeutic drugs between risk groups were calculated to evaluate the sensitivity of immunotherapy. The pathway analysis showed that the ERS risk model was relevant to biosynthesis and metabolism. Consistent clustering based on the ERS-related differentially expressed genes (DEGs) demonstrated that the samples divided into three clusters had significant clinicopathological differences. A risk model consisting of six ERS-related genes was established. The model was verified on GSE39582 and GSE17536 testing datasets. The results showed that ERS risk model was significantly related to TME and immune checkpoint, and these genes enhanced the immunotherapy ability of colon cancer. We established a risk model with ERS-related genes (PMM2, STC2, EIF2AK1, HSPA1A, SLC8A1, KCNQ1), which enhance the sensitivity of immunotherapy for colon cancer. These may provide a new perspective for the treatment of colon cancer.

Senescence-related signatures predict prognosis and response to immunotherapy in colon cancer.

Colorectal cancer (CRC) is one of the most common cancers. Cellular senescence plays a vital role in carcinogenesis by activating many pathways. In this study, we aimed to identify biomarkers for predicting the survival and recurrence of CRC through cellular senescence-related genes. Utilizing The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, RNA-sequencing data and clinical information for CRC were collected. A risk model for predicting overall survival was established based on five differentially expressed genes using least absolute shrinkage and selection operator-Cox regression (LASSO-Cox regression), receiver operating characteristic (ROC), and Kaplan-Meier analyses. The study also delved into both the tumor microenvironment and the response to immunotherapy. Moreover, we gathered clinical sample data from our center in order to confirm the findings of public database analysis. Through ROC and Kaplan-Meier analyses, a risk model was developed using five cellular senescence-related genes [i.e., CDKN2A, SERPINE1, SNAI1, CXCL1, and ETS2] to categorize patients into high- and low-risk groups. In the TCGA-colon adenocarcinoma (COAD) and GEO-COAD cohorts, the high-risk group was associated with a bleaker forecast (P<0.05), immune cell inactivation, and insensitivity to immunotherapy in IMvigor210 database (http://research-pub.gene.com/IMvigor210CoreBiologies/). Clinical samples were then used to confirm that ETS2 and CDKN2A could serve as independent prognostic biomarkers in CRC. Gene signatures related to cellular senescence, specifically involving CDKN2A and ETS2, are emerging as promising biomarkers for predicting CRC prognosis and guiding immunotherapy.

A novel angiogenesis-associated risk score predicts prognosis and characterizes the tumor microenvironment in colon cancer.

Angiogenesis of the tumor microenvironment (TME) can promote the proliferation and metastases of colon cancer (CC). However, there is a lack of bioinformatics analysis to comprehensively clarify the molecular characteristics, immune interaction characteristics and predictive values of angiogenesis characteristics in CC patients. This study aimed to perform a comprehensive elucidation of the correlation between angiogenesis and CC for the purpose of improving the clinical management of CC. Angiogenesis-associated genes (AAGs) were evaluated in the population of CC patients from the Cancer Genome Atlas database and Gene Expression Omnibus dataset. The expression, prognostic role, and immune cell infiltration of AAGs were assessed first. And then we established the AAGs score to further explore the prognosis and treatment response of angiogenesis characteristics in individual patient. Totally, we identified two different molecular subtypes of angiogenesis, and there was a significant difference in the background of genome, expression profiles, prognosis, and characteristics of TME between two subtypes. And the AAGs score was independently associated with over survival in CC patients, the prognostic value was significant and confirmed in the entire cohort. And we also constructed a nomogram based on the risk score and clinical parameters to maximize the predictive ability of the risk score. Additionally, the AAGs score was significantly correlated with the tumor mutation burden score, cancer stem cell score and drug sensitivity. Our study elucidated the role of angiogenesis characteristics in CC and the AAGs score could help clinicians plan for individual management with chemotherapy agents and promote the development of immunotherapy in CC. Prospective studies need to be conducted to further confirm our findings.

A Tumor Environment-Activated Photosensitized Biomimetic Nanoplatform for Precise Photodynamic Immunotherapy of Colon Cancer.

Aggressive nature of colon cancer and current imprecise therapeutic scenarios simulate the development of precise and effective treatment strategies. To achieve this, a tumor environment-activated photosensitized biomimetic nanoplatform (PEG2000-SiNcTI-Ph/CpG-ZIF-8@CM) is fabricated by encapsulating metal-organic framework loaded with developed photosensitizer PEG2000-SiNcTI-Ph and immunoadjuvant CpG oligodeoxynucleotide within fusion cell membrane expressing programmed death protein 1 (PD-1) and cluster of differentiation 47 (CD47). By stumbling across, systematic evaluation, and deciphering with quantum chemical calculations, a unique attribute of tumor environment (low pH plus high concentrations of adenosine 5'-triphosphate (ATP))-activated photodynamic effect sensitized by long-wavelength photons is validated for PEG2000-SiNcTI-Ph/CpG-ZIF-8@CM, advancing the precision of cancer therapy. Moreover, PEG2000-SiNcTI-Ph/CpG-ZIF-8@CM evades immune surveillance to target CT26 colon tumors in mice mediated by CD47/signal regulatory proteins α (SIRPα) interaction and PD-1/programmed death ligand 1 (PD-L1) interaction, respectively. Tumor environment-activated photodynamic therapy realized by PEG2000-SiNcTI-Ph/CpG-ZIF-8@CM induces immunogenic cell death (ICD) to elicit anti-tumor immune response, which is empowered by enhanced dendritic cells (DC) uptake of CpG and PD-L1 blockade contributed by the nanoplatform. The photodynamic immunotherapy efficiently combats primary and distant CT26 tumors, and additionally generates immune memory to inhibit tumor recurrence and metastasis. The nanoplatform developed here provides insights for the development of precise cancer therapeutic strategies.

Constructing and validating a risk model based on neutrophil-related genes for evaluating prognosis and guiding immunotherapy in colon cancer.

Colon cancer is one of the most common digestive tract malignancies. Although immunotherapy has brought new hope to colon cancer patients, there is still a large proportion of patients who do not benefit from immunotherapy. Studies have shown that neutrophils can interact with immune cells and immune factors to affect the prognosis of patients. We first determined the infiltration level of neutrophils in tumors using the CIBERSORT algorithm and identified key genes in the final risk model by Spearman correlation analysis and subsequent Cox analysis. The risk score of each patient was obtained by multiplying the Cox regression coefficient and the gene expression level, and patients were divided into two groups based on the median of risk score. Differences in overall survival (OS) and progression-free survival (PFS) were assessed by Kaplan-Meier survival analysis, and model accuracy was validated in independent dataset. Differences in immune infiltration and immunotherapy were evaluated by immunoassay. Finally, immunohistochemistry and western blotting were performed to verify the expression of the three genes in the colon normal and tumor tissues. We established and validated a risk scoring model based on neutrophil-related genes in two independent datasets, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database, with SLC11A1 and SLC2A3 as risk factors and MMP3 as a protective factor. A new nomogram was constructed and validated by combining clinical characteristics and the risk score model to better predict patients OS and PFS. Immune analysis showed that patients in the high-risk group had immune cell infiltration level, immune checkpoint level and tumor mutational burden, and were more likely to benefit from immunotherapy. The low-risk group showed better OS and PFS than the high-risk group in the neutrophil-related gene-based risk model. Patients in the high-risk group presented higher immune infiltration levels and tumor mutational burden and thus may be more responsive to immunotherapy.

Trends in management and outcomes of colon cancer in the United States over 15 years: Analysis of the National Cancer Database.

Management of colon cancer has changed over the last few decades. We assessed the trends in management and outcomes using the US National Cancer Database (NCDB). A retrospective analysis of all patients with colonic adenocarcinoma between 2005 and 2019 was conducted. The cohort was divided into three equal time periods: Period 1 (2005-2009), Period 2 (2010-2014), and Period 3 (2015-2019) to examine treatment and outcomes trends. The primary outcome was 5-year overall survival (OS). The study included 923,275 patients. A significant increase in patients with stage IV disease was noted in Period 3 compared to Period 1 (47.9% vs. 27.9%, respectively), whereas a reciprocal reduction was seen in patients with locally advanced disease (stage II: 20.8%-12%; stage III: 14.5%-7.7%). Use of immunotherapy significantly increased from 0.3% to 7.6%. Mean 5-year OS increased (43.6 vs. 42.1 months) despite the increase in metastatic disease and longer time from diagnosis to definitive surgery (7 vs. 14 days). A reduction in 30-day readmission (5.1%-4.2%), 30- (3.9%-2.8%), and 90-day mortality (7.1%-5%) was seen. Laparoscopic and robotic surgery increased from 45.8% to 53.1% and 2.9% to 12.7%, respectively. Median postoperative length of hospital stay decreased by 2 days. Rate of positive resection margins (7.2%-6%) and median number of examined lymph nodes (14-16) also improved. Minimally invasive surgery and immunotherapy for colon cancer significantly increased in recent years. Patient outcomes including OS improved over time.

Delivery of Interferon β-Encoding Plasmid via Lipid Nanoparticle Restores Interferon β Expression to Enhance Antitumor Immunity in Colon Cancer.

Type I interferon (IFN-I) plays a critical role in host cancer immunosurveillance, but its expression is often impaired in the tumor microenvironment. We aimed at testing the hypothesis that cationic lipid nanoparticle delivery of interferon β (IFNβ)-encoding plasmid to tumors is effective in restoring IFNβ expression to suppress tumor immune evasion. We determined that IFN-I function in tumor suppression depends on the host immune cells. IFN-I activates the expression of Cxcl9 and Cxcl10 to enhance T cell tumor infiltration. RNA-Seq detected a low level of IFNα13 and IFNβ in colon tumor tissue. scRNA-Seq revealed that IFNβ is expressed in immune cell subsets in non-neoplastic human tissues and to a lesser degree in human colon tumor tissues. Forced expression of IFNα13 and IFNβ in colon tumor cells up-regulates major histocompatibility complex I (MHC I) expression and suppresses colon tumor growth in vivo. In human cancer patients, IFNβ expression is positively correlated with human leukocyte antigen (HLA) expression, and IFN-I signaling activation correlates with the patient response to PD-1 blockade immunotherapy. To translate this finding to colon cancer immunotherapy, we formulated a 1,2-dioleoyl-3-trimethylammonium propane (DOTAP)-cholesterol-encapsulated IFNβ-encoding plasmid (IFNBCOL01). IFNBCOL01 transfects colon tumor cells to express IFNβ to increase the level of MHC I expression. IFNBCOL01 therapy transfects tumor cells and tumor-infiltrating immune cells to produce IFNβ to activate MHC I and granzyme B expression and inhibits colon tumor growth in mice. Our data determine that lipid nanoparticle delivery of IFNβ-encoding plasmid DNA enhances tumor immunogenicity and T cell effector function to suppress colon tumor growth in vivo.

Construction and validation of a colon cancer prognostic model based on tumor mutation burden-related genes

Currently, immunotherapy has entered the clinical diagnosis and treatment guidelines for colon cancer, but existing immunotherapy markers cannot predict the effectiveness of immunotherapy well. This study utilized the TCGA-COAD queue to perform differential gene analysis on high and low-mutation burden samples, and screen differentially expressed genes (DEGs). To explore new molecular markers or predictive models of immunotherapy by using DEGs for NMF classification and prognostic model construction. Through systematic bioinformatics analysis, the TCGA-COAD cohort was successfully divided into high mutation burden subtypes and low mutation burden subtypes by NMF typing using DEGs. The proportion of MSI-H between high mutation burden subtypes was significantly higher than that of low mutation burden subtypes, but there was no significant difference in immunotherapy efficacy between the two subtypes. Drug sensitivity analysis showed significant differences in drug sensitivity between the two subtypes. Subsequently, we constructed a prognostic model using DEGs, which can effectively predict patient survival and immunotherapy outcomes. The prognosis and immunotherapy outcomes of the low-risk group were significantly better than those of the high-risk group. The external dataset validation of the constructed prognostic model using the GSE39582 dataset from the GEO database yielded consistent results. At the same time, we also analyzed the TMB and MSI situation between the high and low-risk groups, and the results showed that there was no significant difference in TMB between the high and low-risk groups, but the proportion of MSI-H in the high-risk group was significantly higher than that in the low-risk group. Finally, we conclude that TMB is not a suitable molecular marker for predicting the efficacy of immunotherapy in colon cancer. The newly constructed prognostic model can effectively differentiate the prognosis of colon cancer patients and predict their immunotherapy efficacy.

A lipid/PLGA nanocomplex to reshape tumor immune microenvironment for colon cancer therapy.

Immune checkpoint blockade therapy provides a new strategy for tumor treatment; however, the insufficient infiltration of cytotoxic T cells and immunosuppression in tumor microenvironment lead to unsatisfied effects. Herein, we reported a lipid/PLGA nanocomplex (RDCM) co-loaded with the photosensitizer Ce6 and the indoleamine 2,3-dioxygenase (IDO) inhibitor 1MT to improve immunotherapy of colon cancer. Arginine-glycine-aspartic acid (RGD) as the targeting moiety was conjugated on 1,2-distearoyl-snglycero-3-phosphoethanolamine lipid via polyethylene glycol (PEG), and programmed cell death-ligand 1 (PD-L1) peptide inhibitor DPPA (sequence: CPLGVRGK-GGG-d(NYSKPTDRQYHF)) was immobilized on the terminal group of PEG via matrix metalloproteinase 2 sensitive peptide linker. The Ce6 and 1MT were encapsulated in PLGA nanoparticles. The drug loaded nanoparticles were composited with RGD and DPPA modified lipid and lecithin to form lipid/PLGA nanocomplexes. When the nanocomplexes were delivered to tumor, DPPA was released by the cleavage of a matrix metalloproteinase 2-sensitive peptide linker for PD-L1 binding. RGD facilitated the cellular internalization of nanocomplexes via avβ3 integrin. Strong immunogenic cell death was induced by 1O2 generated from Ce6 irradiation under 660 nm laser. 1MT inhibited the activity of IDO and reduced the inhibition of cytotoxic T cells caused by kynurenine accumulation in the tumor microenvironment. The RDCM facilitated the maturation of dendritic cells, inhibited the activity of IDO, and markedly recruited the proportion of tumor-infiltrating cytotoxic T cells in CT26 tumor-bearing mice, triggering a robust immunological memory effect, thus effectively preventing tumor metastasis. The results indicated that the RDCM with dual IDO and PD-L1 inhibition effects is a promising platform for targeted photoimmunotherapy of colon cancer.

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.

Prognostic value of fatty acid metabolism-related genes in colorectal cancer and their potential implications for immunotherapy.

Colorectal cancer is one of the most common gastrointestinal cancers and the second leading cause of cancer-related death. Although colonoscopy screening has greatly improved the early diagnosis of colorectal cancer, its recurrence and metastasis are still significant problems. Tumour cells usually have the hallmark of metabolic reprogramming, while fatty acids play important roles in energy storage, cell membrane synthesis, and signal transduction. Many pathways of fatty acid metabolism (FAM) are involved in the occurrence and development of colon cancer, and the complex molecular interaction network contains a variety of genes encoding key enzymes and related products. Clinical information and RNA sequencing data were collected from TCGA and GEO databases. The prognosis model of colon cancer was constructed by LASSO-Cox regression analysis among the selected fatty acid metabolism genes with differential expression. Nomogram for the prognosis model was also constructed in order to analyze its value in evaluating the survival and clinical stage of the colon cancer patients. The differential expression of the selected genes was verified by qPCR and immunohistochemistry. GSEA and GSVA were used to analyze the enrichment pathways for high- and low-risk groups. CIBERSORT was used to analyze the immune microenvironment of colon cancer and to compare the infiltration of immune cells in the high- and low-risk groups. The "circlize" package was used to explore the correlation between the risk score signature and immunotherapy for colon cancer. We analysed the differential expression of 704 FAM-related genes between colon tumour and normal tissue and screened 10 genes with prognostic value. Subsequently, we constructed a prognostic model for colon cancer based on eight optimal FAM genes through LASSO Cox regression analysis in the TCGA-COAD dataset, and its practicality was validated in the GSE39582 dataset. Moreover, the risk score calculated based on the prognostic model was validated as an independent prognostic factor for colon cancer patients. We further constructed a nomogram composed of the risk score signature, age and American Joint Committee on Cancer (AJCC) stage for clinical application. The colon cancer cohort was divided into high- and low-risk groups according to the optimal cut-off value, and different enrichment pathways and immune microenvironments were depicted in the groups. Since the risk score signature was significantly correlated with the expression of immune checkpoint molecules, the prognostic model might be able to predict the immunotherapy response of colon cancer patients. In summary, our findings expand the prognostic value of FAM-related genes in colon cancer and provide evidence for their application in guiding immunotherapy.

A neutrophil extracellular traps-related classification predicts prognosis and response to immunotherapy in colon cancer

Neutrophil extracellular traps (NETs) have been categorized as a form of inflammatory cell death mode of neutrophils (NETosis) involved in natural immunity and the regulation of adaptive immunity. More and more studies revealed the ability of NETs to reshape the tumor immune microenvironment (TIME) by limiting antitumor effector cells, which may impair the efficacy of immunotherapy. To explore whether NETs-related genes make vital impacts on Colon carcinoma (COAD), we have carried out a systematic analysis and showed several findings in the present work. First, we obtained the patient's data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) dataset, aiming to detect two NETs-associated subtypes by consensus clustering. For the purpose of annotating the roles of NETs-related pathways, gene ontology enrichment analyses were adopted. Next, we constructed a 6 novel NETs-related genes score using the Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression model. We found that the NETs risk score was notably upregulated in COAD patient samples, and its levels were notably correlated with tumor clinicopathological and immune traits. Then, according to NETs-associated molecular subtypes and the risk signature, this study compared immune cell infiltration calculated through the estimate, CIBERSORT, TIMER, ssGSEA algorithms, tumor immune dysfunction, as well as exclusion (TIDE). Furthermore, we confirm that MPO(myeloperoxidase) was significantly upregulated in COAD patient samples, and its levels were significantly linked to tumor malignancy and clinic outcome. Moreover, multiplex immunohistochemistry (mIHC) spatial analysis confirmed that MPO was closely related to Treg and PD-1 + Treg in spatial location which suggested MPO may paly an important role in TIME formation. Altogether, the obtained results indicated that a six NETs-related genes prognostic signature was conducive to estimating the prognosis and response of chemo-/immuno-therapy of COAD patients.

Identification of signature of tumor-infiltrating CD8 T lymphocytes in prognosis and immunotherapy of colon cancer by machine learning

BackgroundTo explore the specific marker of CD8+ T cell subsets which are closely related to the prognosis and immunotherapy of patients with colon cancer. Methods18 kinds of immune cell expression profile data sets were obtained from GEO database. Compared with other immune cell types, the specific markers of CD8 (+) T cells (TI-CD8) in colorectal cancer were screened. Regression analyses were used to further screen prognostic related genes and construct a prognostic evaluation model. The patients were stratified and analyzed according to the risk scores, KRAS mutation status, stage, lymphatic infiltration and other indicators. The landscape of infiltration level, mutation and copy number variation of immune subsets in high and low TI-CD8Sig score groups were compared and analyzed. The difference of drug response between high and low TI-CD8Sig score groups was analyzed. Differential expression of the model genes was verified by the HPA database. ResultsSix prognostic-related CD8T cell-specific gene targets were further screened, and the prognostic evaluation model was constructed. The AUC value of the model is >0.75. FAT3 and UNC13C showed a high mutation state in the low-risk group, while USH2A, MUC5B et al. specifically showed a high mutation state in the high-risk group. Compared with the low-risk group, the high-risk group had lower effective rate of drug response. The expression of PD-1 gene was positively correlated with the level of TI-CD8Sig score. ConclusionThe risk assessment model based on CD8T cell-specific marker genes can effectively predict the prognosis and the drug response of patients with CRC.

Harnessing Ag2S quantum dots with immune adjuvant for NIR-II fluorescence imaging-guided sonodynamic immunotherapy of colon cancer

Harnessing Ag2S quantum dots with immune adjuvant for NIR-II fluorescence imaging-guided sonodynamic immunotherapy of colon cancer

Inhibition of neuroactive ligand–receptor interaction pathway can enhance immunotherapy response in colon cancer: an in silico study

ABSTRACT Background The potential mechanism underlying the association between Homologous recombination deficiency (HRD) and immunotherapy in colon cancer has not been investigated. Methods The exon sequencing data and transcriptome data of 456 colon adenocarcinoma (COAD) patients were obtained from the TCGA database. Pathway activity score was calculated by GSVA methods and engaged in further survival analysis. The prognostic value of the candidate pathways was validated in an external GEO cohort and an immunotherapy cohort. Results Patients with high HRD were associated with poor prognosis, lower tumor mutation burden and microsatellite instability, higher fraction genome alteration, and less sensitivity to immunotherapy in COAD. And then, the neuroactive ligand–receptor interaction pathway was over-activated in high-HRD tumors and associated with immunosuppression in colon cancer with high HRD. Besides, the pathway was associated with prognosis and immunotherapy response in COAD. Moreover, genes in this pathway such as LTB4R2 can be used as a novel target for therapy development in colon cancer. Conclusion Our study not only revealed the potential mechanism of HRD and the function of the neuroactive ligand–receptor interaction pathway in colon cancer but also provided new clues for the improvement of immunotherapy response in colon cancer.

Clinical plasma cells-related genes to aid therapy in colon cancer

The tumor immune microenvironment (TIME) of colon cancer (CC) has been associated with extensive immune cell infiltration (IMI). Increasing evidence demonstrated that plasma cells (PC) have an extremely important role in advance of antitumor immunity. Nonetheless, there is a lack of comprehensive analyses of PC infiltration in clinical prognosis and immunotherapy in CC. This study systematically addressed the gene expression model and clinical information of CC patients. Clinical samples were obtained from the TCGA (The Cancer Genome Atlas) databases. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), GSVA, and the MAlignant Tumors using Expression data (ESTIMATE) algorithm were employed to research the potential mechanism and pathways. Immunophenoscore (IPS) was obtained to evaluate the immunotherapeutic significance of risk score. Half maximal inhibitory concentration (IC50) of chemotherapeutic medicine was predicted by employing the pRRophetic algorithm. A total of 513 CC samples (including 472 tumor samples and 41 normal samples) were collected from the TCGA-GDC database. Significant black modules and 313 candidate genes were considered PC-related genes by accessing WGCNA. Five pivotal genes were established through multiple analyses, which revealed excellent prognostic. The underlying correlation between risk score with tumor mutation burden (TMB) was further explored. In addition, the risk score was obviously correlated with various tumor immune microenvironment (TIME). Also, risk CC samples showed various signaling pathways activity and different pivotal sensitivities to administering chemotherapy. Finally, the biological roles of the CD177 gene were uncovered in CC.