Tim-3 is upregulated in human colorectal carcinoma and associated with tumor progression

Yu, Muming; Lü, Bin; Liu, Yan-Cun; Me, Ying; Wang, Lijun; Zhang, Peng

doi:10.3892/mmr.2016.6065

Cited by 50 publications

(47 citation statements)

References 27 publications

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“…Knockdown of TIM-3 in CRC cell lines HCT116 and HT-29 significantly reduced cell proliferation rates compared with controls [9]. TIM-3 also promotes inflammation through the synergetic action with TLR signaling in immune cells [9]. Our network analysis showed that immune cell trafficking/inflammatory response-mediated genes were upregulated in TIM-3 + T cells (Figure 3 and Figure S4A).…”

Section: Discussionmentioning

confidence: 87%

“…The expression of TIM-3 at higher levels in colorectal cancer tissues is significantly associated with tumor size and tumor-node/distant metastasis [9]. Knockdown of TIM-3 in CRC cell lines HCT116 and HT-29 significantly reduced cell proliferation rates compared with controls [9]. TIM-3 also promotes inflammation through the synergetic action with TLR signaling in immune cells [9].…”

Section: Discussionmentioning

confidence: 99%

“…Accumulating evidence suggests that TIM-3 is expressed not only on effector T cells, but also in tumor-infiltrating Tregs in multiple tumor types [8,50]. The increased expression of TIM 3 in tumor-infiltrating Tregs are also associated with poor survival [8,9]. Here we found that in CRC TME, TIM-3 + Tregs have higher expression of FoxP3, CD25, Helios, CCR7, and also co-inhibitory molecules including PD-1, CTLA4, and TIM-3 (Figure 2 and Figure S3).…”

Section: Discussionmentioning

confidence: 99%

“…Reports showed that TIM-3 can activate the TCR signaling more likely towards exhaustion phenotypes with co-expression of other ICs in CRC patients [6,7]. Accumulating evidence suggests that expression of TIM-3 on tumor-infiltrating lymphocytes (TILs) has an indispensable role in tumor biology [8,9]. TIM-3 plays an important role in tumorigenesis and progression of prostate cancer and also has a potential prognostic value as a biomarker [10].…”

mentioning

confidence: 99%

“…TIM-3 plays an important role in tumorigenesis and progression of prostate cancer and also has a potential prognostic value as a biomarker [10]. Moreover, TIM-3 serves as a potential mediator for tumor progression in CRC [9]. The characterization of TIM-3 in various human tumors including hepatocellular, cervical, colorectal, and ovarian carcinomas showed that TIM-3-expressing CD4 + TILs could represent the functional regulatory T cells with highly immunosuppressive characteristics [8].…”

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confidence: 99%

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Transcriptomic Profiling of Tumor-Infiltrating CD4+TIM-3+ T Cells Reveals Their Suppressive, Exhausted, and Metastatic Characteristics in Colorectal Cancer Patients

et al. 2020

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T cell immunoglobulin mucin-3 (TIM-3) is an immune checkpoint identified as one of the key players in regulating T-cell responses. Studies have shown that TIM-3 is upregulated in the tumor microenvironment (TME). However, the precise role of TIM-3 in colorectal cancer (CRC) TME is yet to be elucidated. We performed phenotypic and molecular characterization of TIM-3+ T cells in the TME and circulation of CRC patients by analyzing tumor tissues (TT, TILs), normal tissues (NT, NILs), and peripheral blood mononuclear cells (PBMC). TIM-3 was upregulated on both CD4+ and CD3+CD4− (CD8+) TILs. CD4+TIM-3+ TILs expressed higher levels of T regulatory cell (Tregs)-signature genes, including FoxP3 and Helios, compared with their TIM-3− counterparts. Transcriptomic and ingenuity pathway analyses showed that TIM-3 potentially activates inflammatory and tumor metastatic pathways. Moreover, NF-κB-mediated transcription factors were upregulated in CD4+TIM-3+ TILs, which could favor proliferation/invasion and induce inflammatory and T-cell exhaustion pathways. In addition, we found that CD4+TIM-3+ TILs potentially support tumor invasion and metastasis, compared with conventional CD4+CD25+ Tregs in the CRC TME. However, functional studies are warranted to support these findings. In conclusion, this study discloses some of the functional pathways of TIM-3+ TILs, which could improve their targeting in more specific therapeutic approaches in CRC patients.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Transcriptomic Profiling of Tumor-Infiltrating CD4+TIM-3+ T Cells Reveals Their Suppressive, Exhausted, and Metastatic Characteristics in Colorectal Cancer Patients

et al. 2020

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Relationship between immune checkpoint proteins, tumour microenvironment characteristics, and prognosis in primary operable colorectal cancer

Al‐Badran¹,

Grant²,

Campo³

et al. 2020

The Journal of Pathology CR

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The tumour microenvironment is an important factor for colorectal cancer prognosis, affecting the patient's immune response. Immune checkpoints, which regulate the immune functions of lymphocytes, may provide prognostic power. This study aimed to investigate the prognostic value of the immune checkpoints TIM‐3, LAG‐3 and PD‐1 in patients with stage I–III colorectal cancer. Immunohistochemistry was employed to detect TIM‐3, LAG‐3, PD‐1 and PD‐L1 in 773 patients with stage I–III colorectal cancer. Immune checkpoint protein expression was assessed in tumour cells using the weighted histoscore, and in immune cells within the stroma using point counting. Scores were analysed for associations with survival and clinical factors. High tumoural LAG‐3 (hazard ratio [HR] 1.45 95% confidence interval [CI] 1.00–2.09, p = 0.049) and PD‐1 (HR 1.34 95% CI 1.00–1.78, p = 0.047) associated with poor survival, whereas high TIM‐3 (HR 0.60 95% CI 0.42–0.84, p = 0.003), LAG‐3 (HR 0.58 95% CI 0.40–0.87, p = 0.006) and PD‐1 (HR 0.65 95% CI 0.49–0.86, p = 0.002) on immune cells within the stroma associated with improved survival, while PD‐L1 in the tumour (p = 0.487) or the immune cells within the stroma (p = 0.298) was not associated with survival. Furthermore, immune cell LAG‐3 was independently associated with survival (p = 0.017). Checkpoint expression scores on stromal immune cells were combined into a Combined Immune Checkpoint Stromal Score (CICSS), where CICSS 3 denoted all high, CICSS 2 denoted any two high, and CICSS 1 denoted other combinations. CICSS 3 was associated with improved patient survival (HR 0.57 95% CI 0.42–0.78, p = 0.001). The results suggest that individual and combined high expression of TIM‐3, LAG‐3, and PD‐1 on stromal immune cells are associated with better colorectal cancer prognosis, suggesting there is added value to investigating multiple immune checkpoints simultaneously.

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Soluble Tim3 detection by time‐resolved fluorescence immunoassay and its application in membranous nephropathy

Chen

Wang

et al. 2020

Clinical Laboratory Analysis

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T-cell immunoglobulin and mucin domain 3 (Tim3) is a type 1 transmembrane receptor that can inhibit the activation of T helper 1 (Th1) cells after ligand binding. 1 As a member of the Tim family, Tim3 was originally discovered on activated Th1 and Th17 cells, as well as T cell 1 (Tc1), where it induced T-cell exhaustion or death after binding to galectin-9 (gal-9), 2 partly through the T-cell receptor (TCR) signaling

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Tim-3 is upregulated in human colorectal carcinoma and associated with tumor progression

Cited by 50 publications

References 27 publications

Transcriptomic Profiling of Tumor-Infiltrating CD4+TIM-3+ T Cells Reveals Their Suppressive, Exhausted, and Metastatic Characteristics in Colorectal Cancer Patients

Transcriptomic Profiling of Tumor-Infiltrating CD4+TIM-3+ T Cells Reveals Their Suppressive, Exhausted, and Metastatic Characteristics in Colorectal Cancer Patients

Relationship between immune checkpoint proteins, tumour microenvironment characteristics, and prognosis in primary operable colorectal cancer

Soluble Tim3 detection by time‐resolved fluorescence immunoassay and its application in membranous nephropathy

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