Abstract:Blockade of inhibitory immune checkpoints (ICs) is a promising therapeutic approach; however, it has shown limited success in some cancers including colorectal cancer (CRC). The tumor microenvironment (TME) is largely responsible for response to therapy, and its constituents may provide robust biomarkers for successful immunotherapeutic approaches. In this study, we performed phenotypical characterization and critical analyses of key inhibitory ICs and T regulatory cell (Treg)-related markers on CD4 + T cell s… Show more
“…21 We have previously reported that CD4 + T cell infiltration was significantly higher in the CRC microenvironment, compared with normal tissue with no significant differences between early and advanced stages. 12 In this study, we investigated the transcriptomes and potential functional networks of CD4 + TILs from various stages of CRC. Our analyses led to developing a gene signature based on the transcriptome of CD4 + TILs with a prognostic potential for CRC.…”
Tumor-infiltrating lymphocytes (TILs) play indispensable roles in the progression and response to treatment of solid tumors. However, the prognostic significance of CD4 + TILs is not fully disclosed in cancers generally and in CRC in particular, mainly due to the existence of different functional subsets of CD4 + T cells. We performed transcriptomic profiling of CD4 + TILs isolated from CRC patients in order to identify differentially expressed genes and their functional pathways in early versus advanced disease stages. We found that in advanced stages, genes related to immune and inflammatory responses, in particular Th1mediated immune response and cytotoxicity-mediated genes, were downregulated; while epigeneticmediated silencing genes were upregulated. Interestingly, we identified genes, which were steadily upregulated or downregulated in CD4 + TILs with CRC progression from stage I to IV. Additionally, of the top 200 deregulated genes, 43 upregulated and 64 downregulated genes showed similar deregulation trends in the cancer genome atlas CRC dataset. From these 97 deregulated genes, we identified a "poor prognosis CD4 gene signature (ppCD4sig)". Patients with high ppCD4sig score showed shorter diseasespecific survival (DSS) and progression-free interval (PFI). The ppCD4sig was an independent prognostic indicator for DSS (HR = 1.73, 95% CI 1.32-2.27, P = 0.0001) and PFI (HR = 1.75, 95% CI 1.3-2.35, P = 0.0016). Additionally, patients at advanced stages and at a younger age (<55 years) were more likely to have a high ppCD4sig score. Altogether, our data provide novel insights and a unique prognostic gene signature of CD4 + TILs in the CRC microenvironment.
“…21 We have previously reported that CD4 + T cell infiltration was significantly higher in the CRC microenvironment, compared with normal tissue with no significant differences between early and advanced stages. 12 In this study, we investigated the transcriptomes and potential functional networks of CD4 + TILs from various stages of CRC. Our analyses led to developing a gene signature based on the transcriptome of CD4 + TILs with a prognostic potential for CRC.…”
Tumor-infiltrating lymphocytes (TILs) play indispensable roles in the progression and response to treatment of solid tumors. However, the prognostic significance of CD4 + TILs is not fully disclosed in cancers generally and in CRC in particular, mainly due to the existence of different functional subsets of CD4 + T cells. We performed transcriptomic profiling of CD4 + TILs isolated from CRC patients in order to identify differentially expressed genes and their functional pathways in early versus advanced disease stages. We found that in advanced stages, genes related to immune and inflammatory responses, in particular Th1mediated immune response and cytotoxicity-mediated genes, were downregulated; while epigeneticmediated silencing genes were upregulated. Interestingly, we identified genes, which were steadily upregulated or downregulated in CD4 + TILs with CRC progression from stage I to IV. Additionally, of the top 200 deregulated genes, 43 upregulated and 64 downregulated genes showed similar deregulation trends in the cancer genome atlas CRC dataset. From these 97 deregulated genes, we identified a "poor prognosis CD4 gene signature (ppCD4sig)". Patients with high ppCD4sig score showed shorter diseasespecific survival (DSS) and progression-free interval (PFI). The ppCD4sig was an independent prognostic indicator for DSS (HR = 1.73, 95% CI 1.32-2.27, P = 0.0001) and PFI (HR = 1.75, 95% CI 1.3-2.35, P = 0.0016). Additionally, patients at advanced stages and at a younger age (<55 years) were more likely to have a high ppCD4sig score. Altogether, our data provide novel insights and a unique prognostic gene signature of CD4 + TILs in the CRC microenvironment.
“…10 Similarly, an elevated percentage of CD3 + and CD8 + T cells in colorectal cancer was found to be related to improved OS, whereas a decreased percentage of T-cells was associated with poor prognosis. 41 As shown by Darb-Esfahani and colleagues, the presence of different subpopulations of TILs, including CD4 + and CD8 + T cells, is related to a better prognosis for OC patients. 32 Similar findings have been reported by Webb and co-workers.…”
Aim: Ovarian cancer (OC) is one of the most lethal gynecological malignancies. Recent studies suggest a crucial role of the PD-1/PD-L1 pathway in OC pathogenesis. Therefore, our study aimed at evaluation of the clinical importance of PD-1 expression in ovarian cancer patients. Patients and Methods: In this study, we investigated the role of PD-1 in OC patients (n=50) by analyzing its expression on CD4 + and CD8 + T cells in three OC environments: peripheral blood (PB), peritoneal fluid (PF), and tumor (TT) as well as soluble PD-1 (sPD-1) in plasma and PF in terms of their clinical and prognostic significance. T cells with PD-1 expression were analyzed using flow cytometry. The concentration of sPD-1 was determined with the use of ELISA. Our research demonstrated differences in PD-1 expression on CD4 + and CD8 + T cells in the OC environments. Results: We found an elevated level of CD4 + PD-1 + T cells in tumor and PF, compared to PB. Additionally, we found the highest percentage of CD8 + PD-1 + in tumor, compared to PB and PF. The levels of sPD-1 were higher (p<0.0001) in plasma than in PF. For the first time, we discovered that the higher level of CD4 + PD-1 + T cells in the circulation and the higher sPD-1 level in plasma predict poor survival of OC patients. Conclusion: We suggest that PD-1 could be a predictive biomarker for OC patients and successful immunotherapy.
“…All patients provided written informed consent prior to sample collection. Peripheral blood mononuclear cells (PBMCs) were isolated from fresh blood using Histopaque gradient centrifugation and stored, as previously described ( 17 ). This study was performed under ethics approvals from Hamad Medical Corporation, Doha, Qatar (protocol no.…”
Section: Methodsmentioning
confidence: 99%
“…Isolated PBMCs were stained as previously described ( 17 , 18 ). Briefly, cells were stained with antibodies against CD33–fluorescein isothiocyanate (clone HIM3-4; BD Biosciences, Oxford, UK), HLA DR–phycoerythrin (clone G46-6; BD Biosciences), CD14–phycoerythrin–Cy7 (clone M5E2; BD Biosciences), and CD15–allophycocyanin (clone HI98; BioLegend, San Diego, CA, USA).…”
Section: Methodsmentioning
confidence: 99%
“…7-AAD viability dye (eBioscience, San Diego, CA, USA) was used to identify live cells. The cells were prepared for analyses and sorting as previously described ( 17 , 18 ) Minimal sorter-induced cell stress was ensured following applicable measures, as previously described ( 19 ). FlowJo V10 software (FlowJo, Ashland, OR, USA) was used to perform data analyses.…”
Myeloid-derived suppressor cells (MDSCs) promote tumor immune evasion and favor tumorigenesis by activating various tumor-promoting downstream signals. MDSC expansion is evident in the circulation and tumor microenvironment of many solid tumors including colorectal cancer (CRC). We have recently reported the transcriptomic profiles of tumor-infiltrating MDSCs in CRC patients and uncovered pathways, which could potentially assist tumor progression. In this study, we sorted different subsets of circulating MDSCs in CRC patients and investigated their transcriptomic profiles in order to disclose pathways, which could potentially contribute to disease progression. The sorted subsets included polymorphonuclear/granulocytic MDSCs (PMN-MDSCs), immature MDSCs (I-MDSCs), and monocytic MDSCs (M-MDSCs). Our functional annotation analyses revealed that multiple pathways including DNA damage-, chemotaxis-, apoptosis-, mitogen-activated protein kinase-, transforming growth factor β-, and myeloid differentiation–related transcripts were higher in PMN-MDSCs, compared with monocytic antigen-presenting cells (APCs) or I-MDSCs. Furthermore, genes related to Janus kinase (JAK)–signal transducer and activator of transcription (STAT) were also elevated in PMN-MDSCs. These data suggest that upregulation of JAK-STAT pathway could trigger multiple downstream targets in PMN-MDSCs, which favor tumor progression. Additionally, we found that pathways including phosphatidyl inositol 3-kinase (PI3K), interleukin 6, and TGF-β in M-MDSCs and cell cycle–related pathways in I-MDSCs were upregulated, compared with monocytic APCs. Moreover, acetylation-related genes were upregulated in both PMN-MDSCs and M-MDSCs. This latter finding implicates that epigenetic modifications could also play a role in the regulation of multiple tumor-promoting genes in PMN-MDSCs and M-MDSCs. Taken together, this study reveals various signaling pathways, which regulate the function of MDSC subsets in the circulation of CRC patients. However, functional studies are warranted to support these findings.
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