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Gastric adenocarcinoma (STAD) is characterized by high heterogeneity and aggressiveness, leading to poor prognostic outcomes worldwide. This study explored the prognostic significance of lactylation-related gene sets and mitochondrial functions in STAD by integrating large-scale genomic datasets, including TCGA and several GEO datasets. We utilized Spatial transcriptomics and single-cell RNA sequencing to delineate the tumor microenvironment and assess the heterogeneity of cellular responses within the tumor. Additionally, the study identified distinct molecular subtypes within STAD that correspond with unique survival outcomes and immune profiles, enhancing the molecular classification beyond current paradigms. Prognostic models incorporating these molecular markers demonstrated superior predictive capabilities over existing models across multiple validation datasets. Furthermore, our analysis of immune landscapes revealed that variations in lactylation could influence immune cell infiltration and responsiveness, pointing towards novel avenues for tailored immunotherapy approaches. These comprehensive insights provide a foundation for targeted therapeutic strategies and underscore the potential of metabolic and immune modulation in improving STAD treatment outcomes.

This article is an editorial that discusses new immunotherapy strategies and therapeutic targets for gastrointestinal malignancies. Gastrointestinal malignancies, including cancers of the esophagus, stomach, colorectum, pancreas, and liver, are common and challenging to treat. Current treatment options have limited benefits, and there is a need for more effective therapies. The article highlights the potential of cancer immunotherapy, including immune cell-based therapy, as a promising approach for treating gastrointestinal malignancies. It also emphasizes the importance of identifying prognostic biomarkers that can predict treatment response. The editorial includes a series of original research articles and reviews that explore these topics in detail. [Extracted from the article]

Introduction: Prostate cancer (PCa) shows considerable variation in clinical outcomes between individuals with similar diseases. The initial host-tumor interaction as assessed by detailed analysis of tumor infiltrating immune cells within the primary tumor may dictate tumor evolution and late clinical outcomes. In this study, we assessed the association between clinical outcomes and dendritic cell (DC) or macrophage (MF) tumor infiltration as well as with expression of genes related to their functions. Methods: Infiltration and localization of immature DC, mature DC, total MF and M2-type MF was analyzed by immunohistochemistry in 99 radical prostatectomy specimens from patients with 15.5 years median clinical followup using antibodies against CD209, CD83, CD68 and CD163, respectively. The density of positive cells for each marker in various tumor areas was determined. In addition, expression of immune genes associated with DC and MF was tested in a series of 50 radical prostatectomy specimens by Taqman Low-Density Array with similarly long follow-up. Gene expression was classified as low and high after unsupervised hierarchical clustering. Numbers and ratio of positive cells and levels of gene expression were correlated with endpoints such as biochemical recurrence (BCR), need for definitive androgen deprivation therapy (ADT) or lethal PCa using Cox regression analyses and/or Kaplan-Meier curves. Results: Positive immune cells were observed in tumor, tumor margin, and normal-like adjacent epithelium areas. CD209+ and CD163+ cells were more abundant at the tumor margin. Higher CD209+/CD83+ cell density ratio at the tumor margin was associated with higher risk of ADT and lethal PCa while higher density of CD163+ cells in the normal-like adjacent epithelium was associated with a higher risk of lethal PCa. A combination of 5 genes expressed at high levels correlated with a shorter survival without ADT and lethal PCa. Among these five genes, expression of IL12A and CD163 was correlated to each other and was associated with shorter survival without BCR and ADT/lethal PCa, respectively. Conclusion: A higher level of infiltration of CD209+ immature DC and CD163+ M2-type MF in the peritumor area was associated with late adverse clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: Due to the expanding role of immune checkpoint inhibition in the treatment of head and neck squamous cell carcinoma, understanding immunological processes in the tumor microevironment (TME) has strong translational importance. Though analytical methods for a comprehensive analysis of the immunological TME have constantly improved and expanded over the past years the prognostic relevance of immune cell composition in head and neck cancer TME largely remains ambiguous with most studies focusing on one or a small subset of immune cells. Methods: The overall survival (OS) of the TCGA-HNSC patient cohort comprising 513 head and neck cancer patients was correlated with a total of 29 different immune metrics including a wide spectrum of immune cell subpopulations as well as immune checkpoint receptors and cytokines using RNAseq based immune deconvolution analyses. The most significant predictors of survival among these 29 immune metrics were validated on a separate HNSCC patient cohort (n=101) using immunohistochemistry: CD3, CD20+CXCR5, CD4 +CXCR5, Foxp3 and CD68. Results: Overall immune infiltration irrespective of immune cell composition showed no significant correlation with the patients' overall survival in the TCGAHNSC cohort. However, when focusing on different immune cell subpopulations, naïve B cells (p=0.0006), follicular T-helper cells (p<0.0001), macrophages (p=0.0042), regulatory T cells (p=0.0306), lymphocytes (p=0.0001), and cytotoxic T cells (p=0.0242) were identified as highly significant predictors of improved patient survival. Using immunohistochemical detection of these immune cells in a second independent validation cohort of 101 HNSCC patients, we confirmed the prognostic relevance of follicular T helper cells, cytotoxic T cells and lymphocytes. In multivariable analysis, HPV negativity and advanced UICC stages were identified as additional prognostic biomarkers associated with poor outcome. Conclusion: Our study highlights the prognostic relevance of the immunological tumor environment in head and neck cancer and demonstrates that a more detailed analysis of immune cell composition and immune cell subtypes is necessary to accurately prognosticate. We observed the highest prognostic relevance for lymphocytes, cytotoxic T cells, and follicular T helper cells, suggesting further investigations focusing on these specific immune cell subpopulations not only as predictors of patient prognosis but also as promising targets of new immunotherapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Clear cell renal cell carcinoma (ccRCC) is the most frequently occurring malignant tumor within the kidney cancer subtype. It has low sensitivity to traditional radiotherapy and chemotherapy, the optimal treatment for localized ccRCC has been surgical resection, but even with complete resection the tumor will be eventually developed into metastatic disease in up to 40% of localized ccRCC. For this reason, it is crucial to find early diagnostic and treatment markers for ccRCC. Methods: We obtained anoikis-related genes (ANRGs) integrated from Genecards and Harmonizome dataset. The anoikis-related risk model was constructed based on 12 anoikis-related lncRNAs (ARlncRNAs) and verified by principal component analysis (PCA), Receiver operating characteristic (ROC) curves, and T-distributed stochastic neighbor embedding (t-SNE), and the role of the risk score in ccRCC immune cell infiltration, immune checkpoint expression levels, and drug sensitivity was evaluated by various algorithms. Additionally, we divided patients based on ARlncRNAs into cold and hot tumor clusters using the ConsensusClusterPlus (CC) package. Results: The AUC of risk score was the highest among various factors, including age, gender, and stage, indicating that the model we built to predict survival was more accurate than the other clinical features. There was greater sensitivity to targeted drugs like Axitinib, Pazopanib, and Sunitinib in the high-risk group, as well as immunotherapy drugs. This shows that the risk-scoring model can accurately identify candidates for ccRCC immunotherapy and targeted therapy. Furthermore, our results suggest that cluster 1 is equivalent to hot tumors with enhanced sensitivity to immunotherapy drugs. Conclusion: Collectively, we developed a risk score model based on 12 prognostic lncRNAs, expected to become a new tool for evaluating the prognosis of patients with ccRCC, providing different immunotherapy strategies by screening for hot and cold tumors. [ABSTRACT FROM AUTHOR]

IntroductionProstate cancer (PCa) shows considerable variation in clinical outcomes between individuals with similar diseases. The initial host-tumor interaction as assessed by detailed analysis of tumor infiltrating immune cells within the primary tumor may dictate tumor evolution and late clinical outcomes. In this study, we assessed the association between clinical outcomes and dendritic cell (DC) or macrophage (MΦ) tumor infiltration as well as with expression of genes related to their functions.MethodsInfiltration and localization of immature DC, mature DC, total MΦ and M2-type MΦ was analyzed by immunohistochemistry in 99 radical prostatectomy specimens from patients with 15.5 years median clinical follow-up using antibodies against CD209, CD83, CD68 and CD163, respectively. The density of positive cells for each marker in various tumor areas was determined. In addition, expression of immune genes associated with DC and MΦ was tested in a series of 50 radical prostatectomy specimens by Taqman Low-Density Array with similarly long follow-up. Gene expression was classified as low and high after unsupervised hierarchical clustering. Numbers and ratio of positive cells and levels of gene expression were correlated with endpoints such as biochemical recurrence (BCR), need for definitive androgen deprivation therapy (ADT) or lethal PCa using Cox regression analyses and/or Kaplan-Meier curves.ResultsPositive immune cells were observed in tumor, tumor margin, and normal-like adjacent epithelium areas. CD209+ and CD163+ cells were more abundant at the tumor margin. Higher CD209+/CD83+ cell density ratio at the tumor margin was associated with higher risk of ADT and lethal PCa while higher density of CD163+ cells in the normal-like adjacent epithelium was associated with a higher risk of lethal PCa. A combination of 5 genes expressed at high levels correlated with a shorter survival without ADT and lethal PCa. Among these five genes, expression of IL12A and CD163 was correlated to each other and was associated with shorter survival without BCR and ADT/lethal PCa, respectively.ConclusionA higher level of infiltration of CD209+ immature DC and CD163+ M2-type MΦ in the peritumor area was associated with late adverse clinical outcomes.

BackgroundDue to the expanding role of immune checkpoint inhibition in the treatment of head and neck squamous cell carcinoma, understanding immunological processes in the tumor microevironment (TME) has strong translational importance. Though analytical methods for a comprehensive analysis of the immunological TME have constantly improved and expanded over the past years the prognostic relevance of immune cell composition in head and neck cancer TME largely remains ambiguous with most studies focusing on one or a small subset of immune cells.MethodsThe overall survival (OS) of the TCGA-HNSC patient cohort comprising 513 head and neck cancer patients was correlated with a total of 29 different immune metrics including a wide spectrum of immune cell subpopulations as well as immune checkpoint receptors and cytokines using RNAseq based immune deconvolution analyses. The most significant predictors of survival among these 29 immune metrics were validated on a separate HNSCC patient cohort (n=101) using immunohistochemistry: CD3, CD20+CXCR5, CD4+CXCR5, Foxp3 and CD68.ResultsOverall immune infiltration irrespective of immune cell composition showed no significant correlation with the patients’ overall survival in the TCGA-HNSC cohort. However, when focusing on different immune cell subpopulations, naïve B cells (p=0.0006), follicular T-helper cells (p

BackgroundColon adenocarcinoma (COAD) is a fatal disease, and its cases are constantly increasing worldwide. Further, the therapeutic and management strategies for patients with COAD are still unsatisfactory due to the lack of accurate patient classification and prognostic models. Therefore, our study aims to identify prognostic markers in patients with COAD and construct a cell subtype-specific prognostic model with high accuracy and robustness.MethodsSingle-cell transcriptomic data of six samples were retrieved from the Gene expression omnibus (GEO) database. The cluster annotation and cell-cell communication analysis identified enterocytes as a key player mediating signal communication networks. A four-gene signature prognostic model was constructed based on the enterocyte-related differentially expressed genes (ERDEGs) in patients with COAD of the Cancer Genome Atlas cohort. The prognostic model was validated on three external validation cohorts from the GEO database. The correlation between immune cell infiltration, immunotherapy response, drug sensitivity, and the four-gene signature prognostic model was investigated. Finally, immunohistochemistry (IHC) was performed to determine the expression of the four genes.ResultsWe found that the proportion of epithelial cells was obviously large in COAD samples. Further analysis of epithelial cells showed that the activity of the enterocytes was highest in the cell-cell communication network. Based on enterocyte data, 30 ERDEGs were identified and a 4-gene prognostic model including CPM, CLCA4, ELOVL6, and ATP2A3 was developed and validated. The risk score derived from this model was considered as an independent variable factor to predict overall survival. The patients were divided into high- and low-risk groups based on the median riskscore value. The correlation between immune cell infiltration, immunotherapy response, immune status, clinical characteristics, drug sensitivity, and risk score was analyzed. IHC confirmed the expression of signature genes in tissues from normal individuals, patients with polyps, and COAD.ConclusionIn this study, we constructed and validated a novel four-gene signature prognostic model, which could effectively predict the response to immunotherapy and overall survival in patients with COAD. More importantly, this model provides useful insight into the management of colon cancer patients and aids in designing personalized therapy.

Background: Colon adenocarcinoma (COAD) is a prevalent malignancy that causes significant mortality. Microsatellite instability plays a pivotal function in COAD development and immunotherapy resistance. However, the detailed underlying mechanism requires further investigation. Consequently, identifying molecular biomarkers with prognostic significance and revealing the role of MSI in COAD is important for addressing key obstacles in the available treatments. Methods: CIBERSORT and ESTIMATE analyses were performed to evaluate immune infiltration in COAD samples, followed by correlation analysis for MSI and immune infiltration. Then, differentially expressed genes (DEGs) in MSI and microsatellite stability (MSS) samples were identified and subjected to weighted gene co-expression network analysis (WGCNA). A prognostic model was established with univariate cox regression and LASSO analyses, then evaluated with Kaplan-Meier analysis. The correlation between the prognostic model and immune checkpoint inhibitor (ICI) response was also analyzed. Results: In total, 701 significant DEGs related to MSI status were identified, and WGCNA revealed two modules associated with the immune score. Then, a seven-gene prognostic model was constructed using LASSO and univariate cox regression analyses to predict survival and ICI response. The high-risk score patients in TCGA and GEO cohorts presented a poor prognosis, as well as a high immune checkpoint expression, so they are more likely to benefit from ICI treatment. Conclusion: The seven-gene prognostic model constructed could predict the survival of COAD and ICI response and serve as a reference for immunotherapy decisions. [ABSTRACT FROM AUTHOR]

Background: CLEC5A is a member of the C-type lectin superfamily. It can activate macrophages and lead to a series of immune-inflammation reactions. Previous studies reveal the role of CLEC5A in infection and inflammation diseases. Method: We acquire and analyze data from The Cancer Genome Atlas (TCGA) database, Genotype-Tissue Expression (GTEx) database, and other comprehensive databases via GSCALite, cBioPortal, and TIMER 2.0 platforms or software. Single-cell sequencing analysis was performed for quantifying the tumor microenvironment of several types of cancers. Results: CLEC5A is differentially expressed in a few cancer types, of which overexpression accompanies low overall survival of patients. DNA methylation mainly negatively correlates with CLEC5A expression. Moreover, CLEC5A is positively related to immune infiltration, including macrophages, cancer-associated fibroblasts (CAFs), and regulatory T cells (Tregs). Immune checkpoint genes are significantly associated with CLEC5A expression in diverse cancers. In addition, CLEC5A expression correlates with mismatch repair (MMR) in several cancers. Tumor mutation burden (TMB), microsatellite instability (MSI), and neoantigens show a positive association with CLEC5A expression in several cancers. Furthermore, CLEC5A in cancer correlates with signal transduction, the immune system, EMT, and apoptosis process. The drug sensitivity analysis screens out potential therapeutic agents associated with CLEC5A expression, including FR-180204, Tivozanib, OSI-930, Linifanib, AC220, VNLG/124, Bexarotene, omacetaxine mepesuccinate, narciclasine, leptomycin B, PHA-793887, LRRK2-IN-1, and CR-1-31B. Conclusion: CLEC5A overexpresses in multiple cancers in contrast to normal tissues, and high CLEC5A expression predicts poor prognosis of patients and immune infiltration. CLEC5A is a potential prognostic biomarker of diverse cancers and a target for anti-tumor therapy. [ABSTRACT FROM AUTHOR]

In the present study, the levels of serum and airway soluble chemokines, pro-inflammatory/regulatory cytokines, and growth factors were quantified in critically ill COVID-19 patients (total n=286) at distinct time points (D0, D2-6, D7, D8-13 and D>14-36) upon Intensive Care Unit (ICU) admission. Augmented levels of soluble mediators were observed in serum from COVID-19 patients who progress to death. An opposite profile was observed in tracheal aspirate samples, indicating that systemic and airway microenvironment diverge in their inflammatory milieu. While a bimodal distribution was observed in the serum samples, a unimodal peak around D7 was found for most soluble mediators in tracheal aspirate samples. Systems biology tools further demonstrated that COVID-19 display distinct eccentric soluble mediator networks as compared to controls, with opposite profiles in serum and tracheal aspirates. Regardless the systemic-compartmentalized microenvironment, networks from patients progressing to death were linked to a pro-inflammatory/growth factor-rich, highly integrated center. Conversely, patients evolving to discharge exhibited networks of weak central architecture, with lower number of neighborhood connections and clusters of pro-inflammatory and regulatory cytokines. All in all, this investigation with robust sample size landed a comprehensive snapshot of the systemic and local divergencies composed of distinct immune responses driven by SARS-CoV-2 early on severe COVID-19. [ABSTRACT FROM AUTHOR]

In the present study, the levels of serum and airway soluble chemokines, pro-inflammatory/regulatory cytokines, and growth factors were quantified in critically ill COVID-19 patients (total n=286) at distinct time points (D0, D2-6, D7, D8-13 and D>14-36) upon Intensive Care Unit (ICU) admission. Augmented levels of soluble mediators were observed in serum from COVID-19 patients who progress to death. An opposite profile was observed in tracheal aspirate samples, indicating that systemic and airway microenvironment diverge in their inflammatory milieu. While a bimodal distribution was observed in the serum samples, a unimodal peak around D7 was found for most soluble mediators in tracheal aspirate samples. Systems biology tools further demonstrated that COVID-19 display distinct eccentric soluble mediator networks as compared to controls, with opposite profiles in serum and tracheal aspirates. Regardless the systemic-compartmentalized microenvironment, networks from patients progressing to death were linked to a pro-inflammatory/growth factor-rich, highly integrated center. Conversely, patients evolving to discharge exhibited networks of weak central architecture, with lower number of neighborhood connections and clusters of pro-inflammatory and regulatory cytokines. All in all, this investigation with robust sample size landed a comprehensive snapshot of the systemic and local divergencies composed of distinct immune responses driven by SARS-CoV-2 early on severe COVID-19.

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has shown favorable results in the treatment of hematological malignancies. Despite the use of post-transplant cyclophosphamide (PTCy), graft versus host disease (GVHD) remains as one of the main complications in this setting. Since the skin appears affected in up to 80% of cases of acute GVHD (aGVHD), its prognosis and diagnosis are essential for the correct management of these patients. Plasma concentration of elafin, an elastase inhibitor produced by keratinocytes, has been described elevated at the diagnosis of skin GVHD, correlated with the grade of GVHD, and associated with an increased risk of death. In this study we explored elafin plasma levels in the largest series reported of T cell–replete haplo-HSCT with PTCy. Plasma samples drawn from 87 patients at days +15 and +30 were analyzed (“discovery cohort”). Elafin levels at days +15 were no associated with chronic GVHD, non-relapse mortality, relapse, therapy-resistant GVHD, or overall survival. In our series, elafin levels at day +30 were not associated with post-transplant complications. On the other hand, elafin plasma levels at day +15 were higher in patients with severe skin aGVHD (21,313 vs.14,974 pg/ml; p = 0.01). Of note, patients with higher elafin plasma levels at day +15 presented a higher incidence of stage III-IV skin aGVHD (HR = 18.9; p < 0.001). These results were confirmed (HR = 20.6; p < 0.001) in an independent group of patients (n = 62), i.e. the “validation cohort.” These data suggest that measurement of elafin in patients undergoing haplo-HSCT with PTCy might be useful for an early identification of those patients who are at higher risk of suffering severe skin aGVHD and thus, improve their treatment and prognosis.

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has shown favorable results in the treatment of hematological malignancies. Despite the use of post-transplant cyclophosphamide (PTCy), graft versus host disease (GVHD) remains as one of the main complications in this setting. Since the skin appears affected in up to 80% of cases of acute GVHD (aGVHD), its prognosis and diagnosis are essential for the correct management of these patients. Plasma concentration of elafin, an elastase inhibitor produced by keratinocytes, has been described elevated at the diagnosis of skin GVHD, correlated with the grade of GVHD, and associated with an increased risk of death. In this study we explored elafin plasma levels in the largest series reported of T cell–replete haplo-HSCT with PTCy. Plasma samples drawn from 87 patients at days +15 and +30 were analyzed ("discovery cohort"). Elafin levels at days +15 were no associated with chronic GVHD, non-relapse mortality, relapse, therapy-resistant GVHD, or overall survival. In our series, elafin levels at day +30 were not associated with post-transplant complications. On the other hand, elafin plasma levels at day +15 were higher in patients with severe skin aGVHD (21,313 vs. 14,974 pg/ml; p = 0.01). Of note, patients with higher elafin plasma levels at day +15 presented a higher incidence of stage III-IV skin aGVHD (HR = 18.9; p < 0.001). These results were confirmed (HR = 20.6; p < 0.001) in an independent group of patients (n = 62), i.e. the "validation cohort." These data suggest that measurement of elafin in patients undergoing haplo-HSCT with PTCy might be useful for an early identification of those patients who are at higher risk of suffering severe skin aGVHD and thus, improve their treatment and prognosis. [ABSTRACT FROM AUTHOR]

Serum free light chain (sFLC) is a recently proposed biomarker for CVID diagnosis. Most CVID patients present low or undetectable sFLC up to 10-fold lower compared to other primary antibody deficiencies. Given that κ and λ light chains are normally secreted in excess with respect to immunoglobulins, this finding points to an intrinsic defect of B cell differentiation in CVID. sFLC levels were prospectively evaluated in a cohort of 100 primary immunodeficiency (PID) patients and in 49 patients with secondary immunodeficiency to haematological malignancy (SID). CVID patients had significantly lower κ and/or λ values (mean: κ: 1.39 ± 1.7 mg/L and λ: 1.97 ± 2.24 mg/L) compared to “other PIDs” (κ: 13.97 ± 5.88 mg/L and λ: 12.92 ± 7.4 mg/L, respectively, p < 0.001 both), and SID (κ 20.9 ± 22.8 mg/L and λ 12.8 ± 8.7 mg/L, respectively, p < 0.001 both). The sum of kappa and lambda (sum κ + λ) in CVID patients (7.25 ± 7.90 mg/L) was significantly lower respect to other PIDs (26.44 ± 13.25 mg/L, p < 0.0001), and to SID patients (28.25 ± 26.24 mg/L, p = 0.0002). ROC analysis of the sum κ + λ disclosed an area under the curve (AUC) of 0.894 for CVID diagnosis (SD 0.031; 95% CI: 0.83–0.95, p < 0.0001), with optimal cut-off of 16.7 mg/L, giving the highest combination of sensitivity (92%), specificity (75%) and NPV (98%). The Relative Risk (RR) for patients presenting a sum κ + λ below 16.7 mg/L was 20.35-fold higher (95%, CI: 5.630–75.93) for CVID than below this threshold. A similar behavior of the sFLC in our CVID cohort with respect to previously published studies was observed. We propose a cut-off of sum κ + λ 16.7 with diagnostic application in CVID patients, and discuss potential specific defects converging in low or undetectable sFLC.

Serum free light chain (sFLC) is a recently proposed biomarker for CVID diagnosis. Most CVID patients present low or undetectable sFLC up to 10-fold lower compared to other primary antibody deficiencies. Given that κ and λ light chains are normally secreted in excess with respect to immunoglobulins, this finding points to an intrinsic defect of B cell differentiation in CVID. sFLC levels were prospectively evaluated in a cohort of 100 primary immunodeficiency (PID) patients and in 49 patients with secondary immunodeficiency to haematological malignancy (SID). CVID patients had significantly lower κ and/or λ values (mean: κ: 1.39 ± 1.7 mg/L and λ: 1.97 ± 2.24 mg/L) compared to "other PIDs" (κ: 13.97 ± 5.88 mg/L and λ: 12.92 ± 7.4 mg/L, respectively, p < 0.001 both), and SID (κ 20.9 ± 22.8 mg/L and λ 12.8 ± 8.7 mg/L, respectively, p < 0.001 both). The sum of kappa and lambda (sum κ + λ) in CVID patients (7.25 ± 7.90 mg/L) was significantly lower respect to other PIDs (26.44 ± 13.25 mg/L, p < 0.0001), and to SID patients (28.25 ± 26.24 mg/L, p = 0.0002). ROC analysis of the sum κ + λ disclosed an area under the curve (AUC) of 0.894 for CVID diagnosis (SD 0.031; 95% CI: 0.83–0.95, p < 0.0001), with optimal cut-off of 16.7 mg/L, giving the highest combination of sensitivity (92%), specificity (75%) and NPV (98%). The Relative Risk (RR) for patients presenting a sum κ + λ below 16.7 mg/L was 20.35-fold higher (95%, CI: 5.630–75.93) for CVID than below this threshold. A similar behavior of the sFLC in our CVID cohort with respect to previously published studies was observed. We propose a cut-off of sum κ + λ 16.7 with diagnostic application in CVID patients, and discuss potential specific defects converging in low or undetectable sFLC. [ABSTRACT FROM AUTHOR]

Accumulating evidence highlights natural killer (NK) cell parameters as potential prognostic factors in cancer patients, which provides a strong rationale for developing therapeutic strategies aiming at restoring NK cell. However, reaching this point warrants better characterization of tumor-induced NK cell alterations. Our group recently reported heterogeneous NK maturation in acute myeloid leukemia (AML) patients. However, the clinical significance of such observations remained to be assessed on a larger cohort of patients. NK maturation based on expression of CD56, CD57, and KIR was assessed by flow cytometry in newly diagnosed AML patients (N = 87 patients from GOELAMS-LAM-IR-2006 multicenter trial). Clinical outcome was evaluated with regard to NK maturation profiles. Unsupervised integrated analysis of NK maturation markers confirmed the existence of three distinct groups of patients [hypomaturation (24.1%), intermediate maturation (66.7%), and hypermaturation (9.2%)]. In univariate analysis, significant differences in overall survival (OS) (P = 0.0006) and relapse-free survival (RFS) (P

Accumulating evidence highlights natural killer (NK) cell parameters as potential prognostic factors in cancer patients, which provides a strong rationale for developing therapeutic strategies aiming at restoring NK cell. However, reaching this point warrants better characterization of tumor-induced NK cell alterations. Our group recently reported heterogeneous NK maturation in acute myeloid leukemia (AML) patients. However, the clinical significance of such observations remained to be assessed on a larger cohort of patients. NK maturation based on expression of CD56, CD57, and KIR was assessed by flow cytometry in newly diagnosed AML patients (N = 87 patients from GOELAMS-LAM-IR-2006 multicenter trial). Clinical outcome was evaluated with regard to NK maturation profiles. Unsupervised integrated analysis of NK maturation markers confirmed the existence of three distinct groups of patients [hypomaturation (24.1%), intermediate maturation (66.7%), and hypermaturation (9.2%)]. In univariate analysis, significant differences in overall survival (OS) (P = 0.0006) and relapse-free survival (RFS) (P < 0.0001) were observed among these different groups. Patients with hypomaturation profile had reduced OS, with 3-year OS rates of 12.5 vs 57.1 and 57.4% for patients with intermediate and hypermaturation, respectively. Consistently, patients with hypomaturation profile had reduced RFS, with 3-year RFS rates of 0 vs 52.6 and73.3% for patients with intermediate and hypermaturation, respectively. In multivariate Cox regression models, NK hypomaturation remained significantly associated with reduced OS and RFS, independent of other factors [hazard ratio (HR) = 4.15, P = 0.004 and HR = 8.23, P = 0.003, respectively]. NK maturation defects were further explored by mass cytometry and revealed that NK hypomaturation profile is associated with a reduced frequency of memory-like NK cells. In conclusion, besides classical alterations of NK triggering and inhibitory receptors expression in AML, we confirm that the homeostasis of NK maturation can be modified in the context of AML, notably with a deep maturation blockade in almost 10% patients. [ABSTRACT FROM AUTHOR]

Introduction: Prostate cancer (PCa) shows considerable variation in clinical outcomes between individuals with similar diseases. The initial host-tumor interaction as assessed by detailed analysis of tumor infiltrating immune cells within the primary tumor may dictate tumor evolution and late clinical outcomes. In this study, we assessed the association between clinical outcomes and dendritic cell (DC) or macrophage (MΦ) tumor infiltration as well as with expression of genes related to their functions., Methods: Infiltration and localization of immature DC, mature DC, total MΦ and M2-type MΦ was analyzed by immunohistochemistry in 99 radical prostatectomy specimens from patients with 15.5 years median clinical follow-up using antibodies against CD209, CD83, CD68 and CD163, respectively. The density of positive cells for each marker in various tumor areas was determined. In addition, expression of immune genes associated with DC and MΦ was tested in a series of 50 radical prostatectomy specimens by Taqman Low-Density Array with similarly long follow-up. Gene expression was classified as low and high after unsupervised hierarchical clustering. Numbers and ratio of positive cells and levels of gene expression were correlated with endpoints such as biochemical recurrence (BCR), need for definitive androgen deprivation therapy (ADT) or lethal PCa using Cox regression analyses and/or Kaplan-Meier curves., Results: Positive immune cells were observed in tumor, tumor margin, and normal-like adjacent epithelium areas. CD209 + and CD163 + cells were more abundant at the tumor margin. Higher CD209 + /CD83 + cell density ratio at the tumor margin was associated with higher risk of ADT and lethal PCa while higher density of CD163 + cells in the normal-like adjacent epithelium was associated with a higher risk of lethal PCa. A combination of 5 genes expressed at high levels correlated with a shorter survival without ADT and lethal PCa. Among these five genes, expression of IL12A and CD163 was correlated to each other and was associated with shorter survival without BCR and ADT/lethal PCa, respectively., Conclusion: A higher level of infiltration of CD209 + immature DC and CD163 + M2-type MΦ in the peritumor area was associated with late adverse clinical outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Molina, LaRue, Simonyan, Hovington, Têtu, Fradet, Lacombe, Toren, Bergeron and Fradet.)

Background: Clear cell renal cell carcinoma (ccRCC) is the most frequently occurring malignant tumor within the kidney cancer subtype. It has low sensitivity to traditional radiotherapy and chemotherapy, the optimal treatment for localized ccRCC has been surgical resection, but even with complete resection the tumor will be eventually developed into metastatic disease in up to 40% of localized ccRCC. For this reason, it is crucial to find early diagnostic and treatment markers for ccRCC., Methods: We obtained anoikis-related genes (ANRGs) integrated from Genecards and Harmonizome dataset. The anoikis-related risk model was constructed based on 12 anoikis-related lncRNAs (ARlncRNAs) and verified by principal component analysis (PCA), Receiver operating characteristic (ROC) curves, and T-distributed stochastic neighbor embedding (t-SNE), and the role of the risk score in ccRCC immune cell infiltration, immune checkpoint expression levels, and drug sensitivity was evaluated by various algorithms. Additionally, we divided patients based on ARlncRNAs into cold and hot tumor clusters using the ConsensusClusterPlus (CC) package., Results: The AUC of risk score was the highest among various factors, including age, gender, and stage, indicating that the model we built to predict survival was more accurate than the other clinical features. There was greater sensitivity to targeted drugs like Axitinib, Pazopanib, and Sunitinib in the high-risk group, as well as immunotherapy drugs. This shows that the risk-scoring model can accurately identify candidates for ccRCC immunotherapy and targeted therapy. Furthermore, our results suggest that cluster 1 is equivalent to hot tumors with enhanced sensitivity to immunotherapy drugs., Conclusion: Collectively, we developed a risk score model based on 12 prognostic lncRNAs, expected to become a new tool for evaluating the prognosis of patients with ccRCC, providing different immunotherapy strategies by screening for hot and cold tumors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hao, Li, Lu, He, Shen, Wang and Qiu.)

Background: Colon adenocarcinoma (COAD) is a fatal disease, and its cases are constantly increasing worldwide. Further, the therapeutic and management strategies for patients with COAD are still unsatisfactory due to the lack of accurate patient classification and prognostic models. Therefore, our study aims to identify prognostic markers in patients with COAD and construct a cell subtype-specific prognostic model with high accuracy and robustness., Methods: Single-cell transcriptomic data of six samples were retrieved from the Gene expression omnibus (GEO) database. The cluster annotation and cell-cell communication analysis identified enterocytes as a key player mediating signal communication networks. A four-gene signature prognostic model was constructed based on the enterocyte-related differentially expressed genes (ERDEGs) in patients with COAD of the Cancer Genome Atlas cohort. The prognostic model was validated on three external validation cohorts from the GEO database. The correlation between immune cell infiltration, immunotherapy response, drug sensitivity, and the four-gene signature prognostic model was investigated. Finally, immunohistochemistry (IHC) was performed to determine the expression of the four genes., Results: We found that the proportion of epithelial cells was obviously large in COAD samples. Further analysis of epithelial cells showed that the activity of the enterocytes was highest in the cell-cell communication network. Based on enterocyte data, 30 ERDEGs were identified and a 4-gene prognostic model including CPM , CLCA4 , ELOVL6 , and ATP2A3 was developed and validated. The risk score derived from this model was considered as an independent variable factor to predict overall survival. The patients were divided into high- and low-risk groups based on the median riskscore value. The correlation between immune cell infiltration, immunotherapy response, immune status, clinical characteristics, drug sensitivity, and risk score was analyzed. IHC confirmed the expression of signature genes in tissues from normal individuals, patients with polyps, and COAD., Conclusion: In this study, we constructed and validated a novel four-gene signature prognostic model, which could effectively predict the response to immunotherapy and overall survival in patients with COAD. More importantly, this model provides useful insight into the management of colon cancer patients and aids in designing personalized therapy., Competing Interests: Author YW was employed by GeneScience Pharmaceuticals Co. Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cheng, Wei, Fu, Li and Han.)

The clinical outcome of allogeneic hematopoietic stem cell transplantation (HSCT) is strongly influenced from the potential complications arising during the delicate phase of post-transplant immune restoration. The quantitative aspects of immune-cell repopulation after HSCT and the qualitative features their functional restitution have been extensively reported. Nevertheless, measurable immune biomarkers predicting the clinical outcome of HSCT await formal validation. The aim of this review is an appraisal of most studies published so far on the predictive value of different T and NK-cell biomarkers after HSCT with emphasis on defined thresholds endorsed by multivariate analysis.

Background: Colon adenocarcinoma (COAD) is a prevalent malignancy that causes significant mortality. Microsatellite instability plays a pivotal function in COAD development and immunotherapy resistance. However, the detailed underlying mechanism requires further investigation. Consequently, identifying molecular biomarkers with prognostic significance and revealing the role of MSI in COAD is important for addressing key obstacles in the available treatments., Methods: CIBERSORT and ESTIMATE analyses were performed to evaluate immune infiltration in COAD samples, followed by correlation analysis for MSI and immune infiltration. Then, differentially expressed genes (DEGs) in MSI and microsatellite stability (MSS) samples were identified and subjected to weighted gene co-expression network analysis (WGCNA). A prognostic model was established with univariate cox regression and LASSO analyses, then evaluated with Kaplan-Meier analysis. The correlation between the prognostic model and immune checkpoint inhibitor (ICI) response was also analyzed., Results: In total, 701 significant DEGs related to MSI status were identified, and WGCNA revealed two modules associated with the immune score. Then, a seven-gene prognostic model was constructed using LASSO and univariate cox regression analyses to predict survival and ICI response. The high-risk score patients in TCGA and GEO cohorts presented a poor prognosis, as well as a high immune checkpoint expression, so they are more likely to benefit from ICI treatment., Conclusion: The seven-gene prognostic model constructed could predict the survival of COAD and ICI response and serve as a reference for immunotherapy decisions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sun, Li, Shang, Zhang, Ai and Liu.)

Background: CLEC5A is a member of the C-type lectin superfamily. It can activate macrophages and lead to a series of immune-inflammation reactions. Previous studies reveal the role of CLEC5A in infection and inflammation diseases., Method: We acquire and analyze data from The Cancer Genome Atlas (TCGA) database, Genotype-Tissue Expression (GTEx) database, and other comprehensive databases via GSCALite, cBioPortal, and TIMER 2.0 platforms or software. Single-cell sequencing analysis was performed for quantifying the tumor microenvironment of several types of cancers., Results: CLEC5A is differentially expressed in a few cancer types, of which overexpression accompanies low overall survival of patients. DNA methylation mainly negatively correlates with CLEC5A expression. Moreover, CLEC5A is positively related to immune infiltration, including macrophages, cancer-associated fibroblasts (CAFs), and regulatory T cells (Tregs). Immune checkpoint genes are significantly associated with CLEC5A expression in diverse cancers. In addition, CLEC5A expression correlates with mismatch repair (MMR) in several cancers. Tumor mutation burden (TMB), microsatellite instability (MSI), and neoantigens show a positive association with CLEC5A expression in several cancers. Furthermore, CLEC5A in cancer correlates with signal transduction, the immune system, EMT, and apoptosis process. The drug sensitivity analysis screens out potential therapeutic agents associated with CLEC5A expression, including FR-180204, Tivozanib, OSI-930, Linifanib, AC220, VNLG/124, Bexarotene, omacetaxine mepesuccinate, narciclasine, leptomycin B, PHA-793887, LRRK2-IN-1, and CR-1-31B., Conclusion: CLEC5A overexpresses in multiple cancers in contrast to normal tissues, and high CLEC5A expression predicts poor prognosis of patients and immune infiltration. CLEC5A is a potential prognostic biomarker of diverse cancers and a target for anti-tumor therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Wu, Chen, Liu, Wen, Yu, Zhang, Liu, Zhang, Luo, Zeng and Cheng.)