Beyond bacteria: Role of non-bacterial gut microbiota species in inflammatory bowel disease and colorectal cancer progression.

This letter emphasizes the need to expand discussions on gut microbiome's role in inflammatory bowel disease (IBD) and colorectal cancer (CRC) by including the often-overlooked non-bacterial components of the human gut flora. It highlights how viral, fungal and archaeal inhabitants of the gut respond towards gut dys-biosis and contribute to disease progression. Viruses such as bacteriophages target certain bacterial species and modulate the immune system. Other viruses found associated include Epstein-Barr virus, human papillomavirus, John Cunningham virus, cytomegalovirus, and human herpes simplex virus type 6. Fungi such as Candida albicans and Malassezia contribute by forming tissue-invasive filaments and producing inflammatory cytokines, respectively. Archaea, mainly metha-nogens are also found altering the microbial fermentation pathways. This corres-pondence, thus underscores the significance of considering the pathological and physiological mechanisms of the entire spectrum of the gut microbiota to develop effective therapeutic interventions for both IBD and CRC.

Comprehensive evaluation of immunological attributes and immunotherapy responses of positive T cell function regulators in colorectal cancer.

BACKGROUND: Positive regulators of T-cell function (PTFRs), integral to T-cell proliferation and activation, have been identified as potential prognostic markers in colorectal cancer (CRC). Despite this, their role within the tumor microenvironment (TME) and their response to immunotherapy are not yet fully understood. METHODS: This study delved into PTFR-related CRC subtypes by analyzing four independent transcriptome datasets, emphasizing the most significant prognostic PTFRs. We identified differentially expressed genes (DEGs) between two subtypes and developed a PTFR risk model using LASSO and Cox regression methods. The model's associations with survival time, clinical features, TME characteristics, tumor mutation profiles, microsatellite instability (MSI), cancer stem cell (CSC) index, and responses to chemotherapy, targeted therapy, and immunotherapy were subsequently explored. RESULTS: The PTFR risk model demonstrated a strong predictive capacity for CRC. It facilitated the estimation of immune cell composition, HLA expression levels, immune checkpoint expression, mutation burden, CSC index features, and the effectiveness of immunotherapy. CONCLUSIONS: This study enhances our understanding of the role of PTFRs in CRC progression and introduces an innovative assessment framework for CRC immunotherapy. This framework improves the prediction of treatment outcomes and aids in the customization of therapeutic strategies.

Immunotherapy for colorectal cancer.

Colorectal cancer is the third most common cancer and the second most lethal cancer in the world. The main cause of the disease is due to dietary and behavioral factors. The treatment of this complex disease is mainly based on traditional treatments, including surgery, radiotherapy, and chemotherapy. Due to its high prevalence and high morbidity, more effective treatments with fewer side effects are urgently needed. In recent years, immunotherapy has become a potential therapeutic alternative and one of the fastest-developing treatments. Immunotherapy inhibits tumor growth by activating or enhancing the immune system to recognize and attack cancer cells. This review presents the latest immunotherapies for immune checkpoint inhibitors, cell therapy, tumor-infiltrating lymphocytes, and oncolytic viruses. Some of these have shown promising results in clinical trials and are used in clinical treatment.

Investigation of pre and postoperative Th1/Th2 cytokine balance and novel cytokines in colorectal cancer patients.

Colorectal cancer (CRC) is a major health problem worldwide and is usually detected in advanced stages, although it is highly treatable with early detection. The aim of this study was to examine the serum levels of various cytokines involved in the pathogenesis of CRC. The study included 29 patients and 30 healthy volunteers. Blood samples were collected twice from the patient group, before and after surgery, and these samples were evaluated for interleukin (IL) 4, 10, 23r, 37, 38, 40 and interferon (IFN) gamma levels. The results showed that IL-4 and IL-38 levels were significantly lower in the preoperative serum samples of the patient group compared to the control group (p < 0.001 and p = 0.01, respectively), while IL-4, IL-10, IL-38 and IL-40 levels increased significantly in the postoperative period (p = 0.004, p = 0.02, p = 0.03 and p = 0.004, respectively). These findings may contribute to the development of immunotherapy agents in the treatment of CRC. However, comprehensive studies on larger patient groups are needed to fully understand the role of cytokines in CRC pathogenesis.

Exploring the Role of the Gut Microbiota in Modulating Colorectal Cancer Immunity.

The gut microbiota plays an essential role in maintaining immune homeostasis and influencing the immune landscape within the tumor microenvironment. This review aims to elucidate the interactions between gut microbiota and tumor immune dynamics, with a focus on colorectal cancer (CRC). The review spans foundational concepts of immuno-microbial interplay, factors influencing microbiome composition, and evidence linking gut microbiota to cancer immunotherapy outcomes. Gut microbiota modulates anti-cancer immunity through several mechanisms, including enhancement of immune surveillance and modulation of inflammatory responses. Specific microbial species and their metabolic byproducts can significantly influence the efficacy of cancer immunotherapies. Furthermore, microbial diversity within the gut microbiota correlates with clinical outcomes in CRC, suggesting potential as a valuable biomarker for predicting response to immunotherapy. Conclusions: Understanding the relationship between gut microbiota and tumor immune responses offers potential for novel therapeutic strategies and biomarker development. The gut microbiota not only influences the natural history and treatment response of CRC but also serves as a critical modulator of immune homeostasis and anti-cancer activity. Further exploration into the microbiome's role could enhance the effectiveness of existing treatments and guide the development of new therapeutic modalities.

Enhancing Colorectal Cancer Immunotherapy: The Pivotal Role of Ferroptosis in Modulating the Tumor Microenvironment.

Colorectal cancer (CRC) represents a significant challenge in oncology, with increasing incidence and mortality rates worldwide, particularly among younger adults. Despite advancements in treatment modalities, the urgent need for more effective therapies persists. Immunotherapy has emerged as a beacon of hope, offering the potential for improved outcomes and quality of life. This review delves into the critical interplay between ferroptosis, an iron-dependent form of regulated cell death, and immunotherapy within the CRC context. Ferroptosis's influence extends beyond tumor cell fate, reshaping the tumor microenvironment (TME) to enhance immunotherapy's efficacy. Investigations into Ferroptosis-related Genes (OFRGs) reveal their pivotal role in modulating immune cell infiltration and TME composition, closely correlating with tumor responsiveness to immunotherapy. The integration of ferroptosis inducers with immunotherapeutic strategies, particularly through novel approaches like ferrotherapy and targeted co-delivery systems, showcases promising avenues for augmenting treatment efficacy. Furthermore, the expression patterns of OFRGs offer novel prognostic tools, potentially guiding personalized and precision therapy in CRC. This review underscores the emerging paradigm of leveraging ferroptosis to bolster immunotherapy's impact, highlighting the need for further research to translate these insights into clinical advancements. Through a deeper understanding of the ferroptosis-immunotherapy nexus, new therapeutic strategies can be developed, promising enhanced efficacy and broader applicability in CRC treatment, ultimately improving patient outcomes and quality of life in the face of this formidable disease.

NLRC4, inflammation and colorectal cancer (Review).

Chronic inflammation is recognized as a major risk factor for cancer and is involved in every phase of the disease. Inflammasomes are central to the inflammatory response and play a crucial role in cancer development. The present review summarizes the role of Nod­like receptor C4 (NLRC4) in inflammation and colorectal cancer (CRC). Reviews of the literature were conducted using Web of Science, PubMed and CNKI, with search terms including 'NLRC4', 'colorectal cancer', 'auto­inflammatory diseases' and 'prognosis'. Variants of NLRC4 can cause recessive immune dysregulation and autoinflammation or lead to ulcerative colitis as a heterozygous risk factor. Additionally, genetic mutations in inflammasome components may increase susceptibility to cancer. NLRC4 is considered a tumor suppressor in CRC. The role of NLRC4 in CRC signaling pathways is currently understood to involve five key aspects (caspase 1, NLRP3/IL­8, IL­1ß/IL­1, NAIP and p53). The mechanisms by which NLRC4 is involved in CRC are considered to be threefold (through pyroptosis, apoptosis, necroptosis and PANoptosis; regulating the immune response; and protecting intestinal epithelial cells to prevent CRC). However, the impact of NLRC4 mutations on CRC remains unclear. In conclusion, NLRC4 is a significant inflammasome that protects against CRC through various signaling pathways and mechanisms. The association between NLRC4 mutations and CRC warrants further investigation.

Immune microenvironmental heterogeneity according to tumor DNA methylation phenotypes in microsatellite instability-high colorectal cancers.

The detailed association between tumor DNA methylation, including CpG island methylation, and tumor immunity is poorly understood. CpG island methylator phenotype (CIMP) is observed typically in sporadic colorectal cancers (CRCs) with microsatellite instability-high (MSI-H). Here, we investigated the differential features of the tumor immune microenvironment according to CIMP status in MSI-H CRCs. CIMP-high (CIMP-H) or CIMP-low/negative (CIMP-L/0) status was determined using MethyLight assay in 133 MSI-H CRCs. All MSI-H CRCs were subjected to digital pathology-based quantification of CD3 + /CD8 + /CD4 + /FoxP3 + /CD68 + /CD204 + /CD177 + tumor-infiltrating immune cells using whole-slide immunohistochemistry. Programmed death-ligand 1 (PD-L1) immunohistochemistry was evaluated using the tumor proportion score (TPS) and combined positive score (CPS). Representative cases were analyzed using whole-exome and RNA-sequencing. In 133 MSI-H CRCs, significantly higher densities of CD8 + tumor-infiltrating lymphocytes (TILs) were observed in CIMP-H tumors compared with CIMP-L/0 tumors. PD-L1 TPS and CPS in CIMP-H tumors were higher than in CIMP-L/0 tumors. Next-generation sequencing revealed that, compared with CIMP-L/0 tumors, CIMP-H tumors had higher fractions of CD8 + T cells/cytotoxic lymphocytes, higher cytolytic activity scores, and activated immune-mediated cell killing pathways. In contrast to CIMP-L/0 tumors, most CIMP-H tumors were identified as consensus molecular subtype 1, an immunogenic transcriptomic subtype of CRC. However, there were no differences in tumor mutational burden (TMB) between CIMP-H and CIMP-L/0 tumors in MSI-H CRCs. In conclusion, CIMP-H is associated with abundant cytotoxic CD8 + TILs and PD-L1 overexpression independent of TMB in MSI-H CRCs, suggesting that CIMP-H tumors represent a typical immune-hot subtype and are optimal candidates for immunotherapy in MSI-H tumors.

Epigenetics and immunotherapy in colorectal cancer: progress and promise.

Colorectal cancer (CRC) is a common malignant tumor with the third and second highest incidence and mortality rates among various malignant tumors. Despite significant advancements in the present therapy for CRC, the majority of CRC cases feature proficient mismatch repair/microsatellite stability and have no response to immunotherapy. Therefore, the search for new treatment options holds immense importance in the diagnosis and treatment of CRC. In recent years, clinical research on immunotherapy combined with epigenetic therapy has gradually increased, which may bring hope for these patients. This review explores the role of epigenetic regulation in exerting antitumor effects through its action on immune cell function and highlights the potential of certain epigenetic genes that can be used as markers of immunotherapy to predict therapeutic efficacy. We also discuss the application of epigenetic drug sensitization immunotherapy to develop new treatment options combining epigenetic therapy and immunotherapy.

Identification of PFKFB3 as a key factor in the development of colorectal cancer and immunotherapy resistance.

Resistance to immunotherapy poses a significant challenge in the treatment of colorectal cancer (CRC), and the underlying mechanisms are not fully understood. Recent studies have implicated PFKFB3, a crucial glycolytic enzyme, in shaping the tumor microenvironment in CRC. Our study aimed to systematically study the role of PFKFB3 in CRC. Bioinformatic analysis revealed that PFKFB3 expression is notably elevated in CRC tissues compared to normal counterparts. In vivo experiments confirmed that suppressing PFKFB3 reduces the tumorigenesis of CRC. We identified multiple cancer-associated pathways positively correlated with high expression of PFKFB3, such as epithelial-mesenchymal transition (EMT), hypoxia, KRAS signaling, angiogenesis, PI3K/AKT/mTOR, Hedgehog, and Notch pathways. Additionally, PFKFB3 exhibited significant correlations with various immune-related pathways, including complement, IL-2/STAT5, IL-6/JAK/STAT3, IFN-α/IFN-γ, TGF-ß, and TNF-α/NF-κB, as well as several immunosuppressive cell markers found in regulatory T cells (CCR8, TGFB1, STAT5B, FOXP3), M2 macrophages (CD163, VSIG4, MS4A4A), T cell exhaustion markers (CTLA-4, PDCD1, LAG3), and PD-L1. Intriguingly, increased PFKFB3 expression was observed in PD-L1 blockade-resistant patients and was associated with shorter overall survival. In a nutshell, PFKFB3 plays an important role in CRC tumorigenesis and resistance to immunotherapy. Targeting PFKFB3 inhibits tumor formation and enhances the efficacy of immunotherapy. Our findings underscore the functions of PFKFB3 in CRC, shedding light on both cancer-related and immunosuppressive pathways.

Arginine on immune function and post-operative obstructions in colorectal cancer patients: a meta-analysis.

BACKGROUND: The aim of this study is to investigate the impact of arginine on immune function and postoperative complications in colorectal cancer (CRC) patients. METHODS: We conducted a comprehensive search to identify eligible RCTs in various databases, such as PubMed, Cochrane Library, EMBASE, Web of Science, MEDLINE, China National Knowledge Infrastructure (CNKI), Wanfang, VIP Medicine Information System (VIP), and Chinese Biomedical Database (CBM). This study aimed to examine IgA, IgG, and IgM levels as well as CD4+ and CD8+ counts as well as the CD4+/CD8+ ratio. Anastomotic leaking, length of stay (LOS), and surgical site infection (SSI) were included as secondary outcomes. Stata (StataCorp, version 14.0) was utilized for data analysis. To ensure the results were reliable, we used meta-regression, sensitivity analysis, and publication bias analysis. RESULTS: A total of 24 publications (including 1883 patients) out of 681 that were retrieved fulfilled the inclusion criteria. The arginine group showed notable improvements in humoral immunity, with gains in IgA (SMD=0.45, 95% CI: 0.30-0.60), IgG (SMD=0.80, 95% CI: 0.64-0.96), and IgM (SMD=0.66, 95% CI: 0.39-0.93). With regards to cellular immunity, the arginine group exhibited a substantial increase in the CD4+ T cell count (SMD = 1.03, 95% CI: 0.67-1.38) compared to the control group. However, the CD4+/CD8+ ratio decreased significantly (SMD=1.37, 95% CI: 0.88-1.86) in the same arginine group, indicating a change in the balance between these two cell types. Additionally, the CD8+ T cell count showed a notable decrease (SMD=-0.70, 95% CI: -1.09 to -0.32) in the arginine group when compared to the control group. Anastomotic leakage was also considerably lower in the arginine group (SMD=-0.05, 95% CI: -0.08 to -0.02), the rate of SSIs was lower (RR = -0.02, 95% CI: -0.05-0), and the length of time patients spent in the hospital was shorter (SMD=-0.15, 95% CI: -0.38 to -0.08). CONCLUSIONS: After radiation treatment for CRC, arginine improves immune function and decreases the risk of infection problems. TRIAL REGISTRATION: Registration with PROSPERO for this meta-analysis is number CRD42024520509.

Cross-modal integration of bulk RNA-seq and single-cell RNA sequencing data to reveal T-cell exhaustion in colorectal cancer.

Colorectal cancer (CRC) is a relatively common malignancy clinically and the second leading cause of cancer-related deaths. Recent studies have identified T-cell exhaustion as playing a crucial role in the pathogenesis of CRC. A long-standing challenge in the clinical management of CRC is to understand how T cells function during its progression and metastasis, and whether potential therapeutic targets for CRC treatment can be predicted through T cells. Here, we propose DeepTEX, a multi-omics deep learning approach that integrates cross-model data to investigate the heterogeneity of T-cell exhaustion in CRC. DeepTEX uses a domain adaptation model to align the data distributions from two different modalities and applies a cross-modal knowledge distillation model to predict the heterogeneity of T-cell exhaustion across diverse patients, identifying key functional pathways and genes. DeepTEX offers valuable insights into the application of deep learning in multi-omics, providing crucial data for exploring the stages of T-cell exhaustion associated with CRC and relevant therapeutic targets.

Comprehensive analysis of bulk and single-cell RNA sequencing data reveals Schlafen-5 (SLFN5) as a novel prognosis and immunity.

Recent advancements have elucidated the multifaceted roles of the Schlafen (SLFN) family, including SLFN5, SLFN11, SLFN12, SLFN13, and SLFN14, which are implicated in immunological responses. However, little is known about the roles of this gene family in relation to malignancy development. The current study aimed to explore the diagnostic and prognostic potential of Schlafen family genes in colorectal adenocarcinoma (COAD) through bioinformatics analysis. Leveraging advanced bioinformatics tools of bulk RNA-sequencing and single-cell sequencing, we conducted in-depth analyses of gene expressions, functional enrichment, and survival patterns of patients with colorectal cancer compared to normal tissue. Among Schlafen family genes, the transcription levels of SLFN5 in COAD tissues were significantly elevated and correlated with poor survival outcomes. Furthermore, SLFN5 regulated the immune response via Janus kinase (JAK)/signal transduction and activator of transcription (STAT)/interferon (IFN)-alpha/beta signaling. These chemokines in inflammation are associated with diabetes and metabolism, suggesting their involvement in altered cellular energetics for COAD progress. In addition, an immune cell deconvolution analysis indicated a correlation between SLFN5 expression and immune-related cell populations, such as regulatory T cells (Tregs). These findings highlighted the potential clinical significance of SLFN5 in COAD and provided insights into its involvement in the tumor microenvironment and immune regulation. Meanwhile, the drug discovery data of SFLN5 with potential targeted small molecules suggested its therapeutic potential for COAD. Collectively, the current research demonstrated that SFLN5 play crucial roles in tumor development and serve as a prospective biomarker for COAD.

Oncolytic adenovirus encoding decorin and CD40 ligand inhibits tumor growth and liver metastasis via immune activation in murine colorectal tumor model.

Colorectal cancer (CRC) is the second common cause of cancer mortality worldwide, and it still lacks effective approaches for relapsed and metastatic CRC. Recently, oncolytic virus has been emerged as a promising immune therapeutic strategy. In this study, we develop a novel oncolytic adenovirus, rAd.mDCN.mCD40L, which drive oncolytic activity by telomerase reverse transcriptase promoter (TERTp). rAd.mDCN.mCD40L expressed both mouse genes of decorin (mDCN) and CD40 ligand (mCD40L), and produced effective cytotoxicity in both human and mouse CRC cells. Moreover, oncolytic adenovirus mediated mDCN over-expression inhibited Met expression in vitro. In CT26 subcutaneous tumor model, intratumorally delivery of oncolytic adenoviruses could inhibit tumor growth and liver metastasis, while mDCN and/or mCD40L armed oncolytic adenoviruses produced much more impressive responses. No obvious toxicity was detected in lung, liver and spleen. Moreover, mDCN and/or mCD40L armed oncolytic adenoviruses altered the immune state to activate anti-tumor responses, including increasing CD8+ T effector cells and CD4+ memory T cells, reducing MDSCs and Tregs in peripheral blood. Furthermore, mDCN and/or mCD40L armed oncolytic adenoviruses mediated mDCN and/or mCD40L expression in tumors, and up-regulated Th1 cytokines and reduced Th2 cytokines in tumors, which will be benefit for remodeling tumor microenvironment. Importantly, rAd.mDCN.mCD40L and rAd.mCD40L prevented tumor liver metastasis much more effectively than rAd.Null and rAd.mDCN. Therefore, rAd.mDCN.mCD40L and rAd.mCD40L are promising approaches for CRC therapy.

CD8α Structural Domains Enhance GUCY2C CAR-T Cell Efficacy.

Despite success in treating some hematological malignancies, CAR-T cells have not yet produced similar outcomes in solid tumors due, in part, to the tumor microenvironment, poor persistence, and a paucity of suitable target antigens. Importantly, the impact of the CAR components on these challenges remains focused on the intracellular signaling and antigen-binding domains. In contrast, the flexible hinge and transmembrane domains have been commoditized and are the least studied components of the CAR. Here, we compared the hinge and transmembrane domains derived from either the CD8ɑ or CD28 molecule in identical GUCY2C-targeted third-generation designs for colorectal cancer. While these structural domains do not contribute to differences in antigen-independent contexts, such as CAR expression and differentiation and exhaustion phenotypes, the CD8ɑ structural domain CAR has a greater affinity for GUCY2C. This results in increased production of inflammatory cytokines and granzyme B, improved cytolytic effector function with low antigen-expressing tumor cells, and robust anti-tumor efficacy in vivo compared with the CD28 structural domain CAR. This suggests that CD8α structural domains should be considered in the design of all CARs for the generation of high-affinity CARs and optimally effective CAR-T cells in solid tumor immunotherapy.

UCN-Centric Prognostic Model for Predicting Overall Survival and Immune Response in Colorectal Cancer.

Colorectal cancer (CRC), a prevalent malignancy, ranks third in global incidence and second in mortality rates. Despite advances in screening methods such as colonoscopy, the accurate diagnosis of CRC remains challenging due to the absence of reliable biomarkers. This study aimed to develop a robust prognostic model for precise CRC outcome prediction. Employing weighted co-expression network analysis (WGCNA) and Cox regression analysis on data from The Cancer Genome Atlas (TCGA), we identified a panel of 12 genes strongly associated with patient survival. This gene panel facilitated accurate CRC outcome predictions, which is also validated via the external validation cohort GSE17536. We conducted further investigations into the key gene, urocortin (UCN), using single-cell transcriptomic data and immune infiltration analysis in CRC patients. Our results revealed a significant correlation between high UCN expression and the reduced prevalence of key immune cells, including B cells, CD4+ cytotoxic T cells, CD8+ T cells, and NKT cells. Functional experiments showed that UCN gene interference in the CRC cell lines significantly decreased cancer cell proliferation, underscoring UCN's role in intestinal immunity modulation. The UCN-centric prognostic model developed enhances prognosis prediction accuracy and offers critical insights for CRC diagnosis and therapeutic interventions.

Increased levels of anti-Encephalitozoon intestinalis antibodies in patients with colorectal cancer.

BACKGROUND: The prevalence of microsporidiosis in the general population, or within specific groups of individuals/patients, is largely underestimated. The absence of specific seroprevalence tools limits knowledge of the epidemiology of these opportunistic pathogens, although known since the 1980s. Since microsporidia hijack the machinery of its host cell and certain species multiply within intestinal cells, a potential link between the parasite and colorectal cancer (CRC) has been suggested. METHODOLOGY/PRINCIPAL FINDINGS: To explore a potential epidemiological link between microsporidia and CRC, we evaluated the seroprevalence of Encephalitozoon intestinalis among CRC patients and healthy subjects using ELISA assays based on two recombinant proteins, namely rEiPTP1 and rEiSWP1, targeting polar tube and spore wall proteins. ELISA were performed in 141 CRC patients and 135 healthy controls. Patients with CRC had significantly higher anti-rEiPTP1 IgG levels than subjects in the control group. Anti-rEiPTP1 IgG, anti-rEiSWP1 IgG and anti-rEiPTP1 IgA levels were significantly increased among men with CRC compared to healthy men. Women with CRC who had died had higher rEiSWP1 IgG levels than those who were still alive. CONCLUSIONS/SIGNIFICANCE: These higher antibody levels against microsporidia in patients with CRC suggest a relationship between microsporidia and pathophysiology of CRC.

ZYG11B participates in the modulation of colorectal cancer cell proliferation and immune infiltration and is a prognostic biomarker.

PROPOSE: The biological function of ZYG11B is still unclear, and few studies on ZYG11B in colorectal cancer were reported. The purpose of our research is to detect the biological functions of ZYG11B in colorectal cancer through The Cancer Genome Atlas (TCGA) database online and the vitro cell experiments. METHODS: The information of ZYG11B in colorectal cancer were downloaded from TCGA database. The bioinformatics analysis has been utilized to examine the expression, functional enrichment, association of immune, clinicopathological characteristics and diagnostic prognostic value. CCK-8 and apoptosis assays have been utilized to identify the abilities of progression and apoptosis. The abilities of invasion and migration were detected by transwell assay. RESULTS: In contrast to adjacent normal tissues, colorectal cancer tissues exhibited a notably diminished expression of ZYG11B (p < 0.001). Further examination through functional enrichment analysis unveiled the enrichment of various pathways associated with tumor proliferation and apoptosis. The implementation of CCK-8 and apoptosis assays validated the suppressive impact of ZYG11B on the progression of colorectal cancer cells (p < 0.001). A significant positive correlation was found between ZYG11B and Tcm and T helper cells (R ≥ 0.3, p < 0.001). Moreover, the expression of ZYG11B demonstrated a prominent presence among subjects without previous experience of colon polyps (p < 0.05), devoid of lymphatic infiltration (p < 0.01), and age ≤ 65 years (p < 0.01). Additionally, ZYG11B exhibited higher expression levels among patients diagnosed with colorectal adenocarcinoma (p < 0.05). Following the analysis of survival prognosis, it became evident that increased ZYG11B expression correlated with enhanced survival rates (p < 0.01) and the ability to accurately forecast the prognosis and survival of COAD/READ patients. CONCLUSION: ZYG11B plays a tumor suppressive role in the proliferation process of colorectal cancer and may have a broad application prospect in the diagnosis and prognosis evaluation of colorectal cancer with more study.

CD8 + T-cells restrict the development of peritoneal metastasis and support the efficacy of hyperthermic intraperitoneal chemotherapy (HIPEC).

Multimodal therapy for peritoneal metastasis (PM) including cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) provides long-term survival in highly selected colorectal cancer patients. Mechanisms behind HIPEC are unknown and may include induction of adaptive immunity. We therefore analyzed human PM samples and explored the impact of HIPEC in experimental models. Human samples from colorectal primary tumors (n = 19) and PM lesions (n = 37) were examined for the presence of CD8 + T-cells and their association with disease free (DFS) and overall survival (OS). CD8 + T cell response after HIPEC was assessed using an in-vivo PM mouse model, tumor cell lines and patient-derived tumor organoids. Patients with high intraepithelial CD8 + T cell counts showed longer DFS and OS. In the mouse model, HIPEC controlled growth of PM and increased numbers of functional granzyme positive CD8 + T cells within tumors. Cell lines and human organoids that were treated with heated chemotherapies showed immunogenic changes, reflected by significantly higher levels of MHC-class I molecules and expression of Cancer Testis Antigens Cyclin A1 and SSX-4. Using in-vitro co-culture assays, we noticed that cancer cells treated with heated chemotherapy primed dendritic cells, which subsequently enhanced effector functions of CD8 + T cells. The presence of CD8 + T-cells within PM lesions is associated with prolonged survival of patients with PM. Data from PM mouse model and in-vitro assay show that heated chemotherapies induce immunogenic changes on cancer cells leading to induction of CD8 + T-cells mediated immunity, which seems to control growth of PM lesions in mice after HIPEC.

Functional gene signature offers a powerful tool for characterizing clinicopathological features and depicting tumor immune microenvironment of colorectal cancer.

BACKGROUND: Colorectal cancer, a prevalent malignancy worldwide, poses a significant challenge due to the lack of effective prognostic tools. In this study, we aimed to develop a functional gene signature to stratify colorectal cancer patients into different groups with distinct characteristics, which will greatly facilitate disease prediction. RESULTS: Patients were stratified into high- and low-risk groups using a prediction model built based on the functional gene signature. This innovative approach not only predicts clinicopathological features but also reveals tumor immune microenvironment types and responses to immunotherapy. The study reveals that patients in the high-risk group exhibit poorer pathological features, including invasion depth, lymph node metastasis, and distant metastasis, as well as unfavorable survival outcomes in terms of overall survival and disease-free survival. The underlying mechanisms for these observations are attributed to upregulated tumor-related signaling pathways, increased infiltration of pro-tumor immune cells, decreased infiltration of anti-tumor immune cells, and a lower tumor mutation burden. Consequently, patients in the high-risk group exhibit a diminished response to immunotherapy. Furthermore, the high-risk group demonstrates enrichment in extracellular matrix-related functions and significant infiltration of cancer-associated fibroblasts (CAFs). Single-cell transcriptional data analysis identifies CAFs as the primary cellular type expressing hub genes, namely ACTA2, TPM2, MYL9, and TAGLN. This finding is further validated through multiple approaches, including multiplex immunohistochemistry (mIHC), polymerase chain reaction (PCR), and western blot analysis. Notably, TPM2 emerges as a potential biomarker for identifying CAFs in colorectal cancer, distinguishing them from both colorectal cancer cell lines and normal colon epithelial cell lines. Co-culture of CAFs and colorectal cancer cells revealed that CAFs could enhance the tumorigenic biofunctions of cancer cells indirectly, which could be partially inhibited by knocking down CAF original TPM2 expression. CONCLUSIONS: This study introduces a functional gene signature that effectively and reliably predicts clinicopathological features and the tumor immune microenvironment in colorectal cancer. Moreover, the identification of TPM2 as a potential biomarker for CAFs holds promising implications for future research and clinical applications in the field of colorectal cancer.