Relevance of Regulatory T Cells during Colorectal Cancer Development

Olguín, Jonadab E.; Medina-Andrade, Itzel; Rodríguez, Tonathiu; Rodrı́guez-Sosa, Miriam; Terrazas, Luis I.

doi:10.3390/cancers12071888

Cited by 42 publications

(33 citation statements)

References 135 publications

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“…However, at Day 68, the Treg cells frequency dropped in STAT6 −/− AOM/DSS animals to similar levels as those in control mice, which is consistent with the fact that there was a lower tumor load ( Figure 1 C–F). Given that the secretion of suppressive cytokines, such as TGF-β and IL-10, has been considered a mechanism used by Treg cells to suppress the immune responses [ 14 ], we decided to evaluate whether Treg cells isolated from spleens with early-stage CAC development (Day 20) may show a different expression of these cytokines under STAT6 deficiency. As shown in Figure 1 G,H, at Day 20 of the CAC progression, we observed a higher expression of TGF-β and IL-10 cytokines in CD4+CD25+Foxp3+ cells ( Figure 1 H) from STAT6 −/− AOM/DSS compared to WT AOM/DSS mice.…”

Section: Resultsmentioning

confidence: 99%

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STAT6 Is Critical for the Induction of Regulatory T Cells In Vivo Controlling the Initial Steps of Colitis-Associated Cancer

Delgado‐Ramirez

Ocaña-Soriano

Ledesma-Soto

et al. 2021

IJMS

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Inflammation is the main driver of the tumor initiation and progression in colitis-associated colorectal cancer (CAC). Recent findings have indicated that the signal transducer and activator of transcription 6 (STAT6) plays a fundamental role in the early stages of CAC, and STAT6 knockout (STAT6−/−) mice are highly resistant to CAC development. Regulatory T (Treg) cells play a major role in coordinating immunomodulation in cancer; however, the role of STAT6 in the induction and function of Treg cells is poorly understood. To clarify the contribution of STAT6 to CAC, STAT6−/− and wild type (WT) mice were subjected to an AOM/DSS regimen, and the frequency of peripheral and local Treg cells was determined during the progression of CAC. When STAT6 was lacking, a remarkable reduction in tumor growth was observed, which was associated with decreased inflammation and an increased number of CD4+CD25+Foxp3+ cells in the colon, circulation, and spleen, including an over-expression of TGF-beta, IL-10, and Foxp3, compared to WT mice, during the early stages of CAC development. Conversely, WT mice showed an inverse frequency of Treg cells compared with STAT6−/− mice, which was followed by intestinal tumor formation. Increased mucosal inflammation, histological damage, and tumorigenesis were restored to levels observed in WT mice when an early inhibition/depletion of Treg cells was performed in STAT6−/− mice. Thus, with STAT6 deficiency, an increased number of Treg cells induce resistance against tumorigenesis, arresting tumor-promoting inflammation. We reported a direct role of STAT6 in the induction and function of Treg cells during CAC development and suggest that STAT6 is a potential target for the modulation of immune response in colitis and CAC.

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Section: Resultsmentioning

confidence: 99%

“…Regulatory T (Treg) cells play a major role in coordinating immunomodulation during CRC [ 14 ]. Foxp3 is a transcription factor essential for the initiation and maintenance of the Treg-suppressive phenotype.…”

Section: Introductionmentioning

confidence: 99%

STAT6 Is Critical for the Induction of Regulatory T Cells In Vivo Controlling the Initial Steps of Colitis-Associated Cancer

Delgado‐Ramirez

Ocaña-Soriano

Ledesma-Soto

et al. 2021

IJMS

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“…The persistence of antitumor immunotherapy is related to the number of CD4 memory T cell [ 46 ]. Treg play a major role in orchestrating immunomodulation during CRC [ 47 ]. Treg cells can inhibit an anti-tumor specific immune response in patients with CRC and is associated with tumor progression during CRC [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Immune landscape and prognostic immune-related genes in KRAS-mutant colorectal cancer patients

et al. 2021

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Background KRAS gene is the most common type of mutation reported in colorectal cancer (CRC). KRAS mutation-mediated regulation of immunophenotype and immune pathways in CRC remains to be elucidated. Methods 535 CRC patients were used to compare the expression of immune-related genes (IRGs) and the abundance of tumor-infiltrating immune cells (TIICs) in the tumor microenvironment between KRAS-mutant and KRAS wild-type CRC patients. An independent dataset included 566 cases of CRC and an in-house RNA sequencing dataset were served as validation sets. An in-house dataset consisting of 335 CRC patients were used to analyze systemic immune and inflammatory state in the presence of KRAS mutation. An immue risk (Imm-R) model consist of IRG and TIICs for prognostic prediction in KRAS-mutant CRC patients was established and validated. Results NF-κB and T-cell receptor signaling pathways were significantly inhibited in KRAS-mutant CRC patients. Regulatory T cells (Tregs) was increased while macrophage M1 and activated CD4 memory T cell was decreased in KRAS-mutant CRC. Prognosis correlated with enhanced Tregs, macrophage M1 and activated CD4 memory T cell and was validated. Serum levels of hypersensitive C-reactive protein (hs-CRP), CRP, and IgM were significantly decreased in KRAS-mutant compared to KRAS wild-type CRC patients. An immune risk model composed of VGF, RLN3, CT45A1 and TIICs signature classified CRC patients with distinct clinical outcomes. Conclusions KRAS mutation in CRC was associated with suppressed immune pathways and immune infiltration. The aberrant immune pathways and immune cells help to understand the tumor immune microenvironments in KRAS-mutant CRC patients.

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“…FOXP3 can also be expressed in dividing, activated T effector cells 47,48 . Apart from FOXP3, some Treg subtypes can express other molecules that increase their immuno-suppressive capacity, and these highly suppressive Treg cells have been detected in CRC patients 49,50,51 . Therefore, relying solely on FOXP3 as a marker of Tregs may be the cause of some of the inconsistencies in the literature regarding Treg and CRC prognosis.…”

Section: Discussionmentioning

confidence: 99%

Stratification of Chemotherapy-Treated Stage III Colorectal Cancer Patients Using Multiplexed Imaging and Single Cell Analysis of T Cell Populations

Stachtea

Loughrey

Salvucci

et al. 2021

Preprint

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Colorectal cancer (CRC) has one of the highest cancer incidences and mortality rates. In stage III, postoperative chemotherapy benefits <20% of patients, while more than 50% will develop distant metastases. Predictive biomarkers for identification of patients with increased risk for disease recurrence are currently lacking, with progress in biomarker discovery hindered by the inherent heterogeneity of the disease. The immune profile of colorectal tumors has previously been found to have prognostic value. The aims of this study were to evaluate immune signatures in the tumor microenvironment (TME) using an in situ multiplexed immunofluorescence imaging and single cell analysis technology (Cell DIVE™). Tissue microarrays (TMAs) with up to three 1mm diameter cores per patient were prepared from 117 stage III CRC patients treated with adjuvant fluoropyrimidine/oxaliplatin chemotherapy. Single sections underwent multilplexed immunofluorescence with Cy3- and Cy5-conjugated antibodies for immune cell markers (CD45, CD3, CD4, CD8, FOXP3, PD1) and cell segmentation markers (DAPI, pan-cytokeratin, AE1, NaKATPase and S6). We applied a probabilistic multi-class, multi-label classification algorithm based on multi-parametric models to build statistical models of protein expression to classify immune cells. Expert annotations of immune cell markers were made on a range of images, and Support Vector Machines (SVM) were used to derive a statistical model for cell classification. Images were also manually scored independently by a Pathologist as "high", "moderate" or "low", for stromal and total immune cell content. Excellent agreement was found between manual and total automated scores (p<0.0001). Higher levels of multi-marker classified regulatory T cells (CD3+CD4+FOXP3+PD1-) were significantly associated with disease-free survival (DFS) and overall-survival (OS) (p=0.049 and 0.032), compared to FOXP3 alone. Our results also showed that PD1- Tregs rather than PD1+ Tregs were associated with improved survival. Overall, compared to single markers, multi-marker classification provided more accurate quantitation of immune cells with greater potential for predicting patient outcomes.

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Relevance of Regulatory T Cells during Colorectal Cancer Development

Cited by 42 publications

References 135 publications

STAT6 Is Critical for the Induction of Regulatory T Cells In Vivo Controlling the Initial Steps of Colitis-Associated Cancer

STAT6 Is Critical for the Induction of Regulatory T Cells In Vivo Controlling the Initial Steps of Colitis-Associated Cancer

Immune landscape and prognostic immune-related genes in KRAS-mutant colorectal cancer patients

Stratification of Chemotherapy-Treated Stage III Colorectal Cancer Patients Using Multiplexed Imaging and Single Cell Analysis of T Cell Populations

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