PD-1+ CD8+ T cells are exhausted in tumours and functional in draining lymph nodes of colorectal cancer patients

Wu, Xi; Zhang, H; Xing, Q.; Cui, Jian; Li, J; Li, Y; Tan, Yan; Wang, S

doi:10.1038/bjc.2014.416

Cited by 97 publications

(92 citation statements)

References 27 publications

(36 reference statements)

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“…5B). Consistent with what others reported on IFN-γ production by CD8 + TIL in primary CRC patients, 49 , 50 our results demonstrate a certain degree of dysfunctionality of intra-tumoral CD4 + Th and CD8 + CTL in MMR-proficient LM-CRC, which may be at least partly due to inhibitory checkpoint interactions between T cells and APC subsets in the TIL cultures, but not complete dysfunctionality.…”

Section: Discussionsupporting

confidence: 92%

Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer

et al. 2018

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Purpose: Liver metastasis develops in >50% of patients with colorectal cancer (CRC), and is a leading cause of CRC-related mortality. We aimed to identify which inhibitory immune checkpoint pathways can be targeted to enhance functionality of intra-tumoral T-cells in mismatch repair-proficient liver metastases of colorectal cancer (LM-CRC). Methodology: Intra-tumoral expression of multiple inhibitory molecules was compared among mismatch repair-proficient LM-CRC, peritoneal metastases of colorectal cancer (PM-CRC) and primary CRC. Expression of inhibitory molecules was also analyzed on leukocytes isolated from paired resected metastatic liver tumors, tumor-free liver tissues, and blood of patients with mismatch repair-proficient LM-CRC. The effects of blocking inhibitory pathways on tumor-infiltrating T-cell responses were studied in ex vivo functional assays. Results: Mismatch repair-proficient LM-CRC showed higher expression of inhibitory receptors on intra-tumoral T-cells and contained higher proportions of CD8+ T-cells, dendritic cells and monocytes than mismatch repair-proficient primary CRC and/or PM-CRC. Inhibitory receptors LAG3, PD-1, TIM3 and CTLA4 were higher expressed on CD8+ T-cells, CD4+ T-helper and/or regulatory T-cells in LM-CRC tumors compared with tumor-free liver and blood. Antibody blockade of LAG3 or PD-L1 increased proliferation and effector cytokine production of intra-tumoral T-cells isolated from LM-CRC in response to both polyclonal and autologous tumor-specific stimulations. Higher LAG3 expression on intra-tumoral CD8+ T-cells associated with longer progression-free survival of LM-CRC patients. Conclusion: Mismatch repair-proficient LM-CRC may be more sensitive to immune checkpoint inhibitors than mismatch repair-proficient primary CRC. Blocking LAG3 enhances tumor-infiltrating T-cell responses of mismatch repair-proficient LM-CRC, and therefore may be a new promising immunotherapeutic target for LM-CRC.

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Section: Discussionsupporting

confidence: 92%

Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer

et al. 2018

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“…T cells in the peripheral blood, tumor-draining lymph nodes and tumor tissue of CRC patients have been shown to have an exhausted phenotype, 20,23,24 including a higher frequency of PD-1 C T cells in tumor compared to adjacent uninvolved bowel. 10 However, analysis of multiple inhibitory receptors on T cells from tumor compared to T cells from NTB has not previously been published.…”

Section: Discussionmentioning

confidence: 99%

Functional impairment of infiltrating T cells in human colorectal cancer

et al. 2016

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T cells play a crucial role in preventing the growth and spread of colorectal cancer (CRC). However, immunotherapies against CRC have only shown limited success, which may be due to lack of understanding about the effect of the local tumor microenvironment (TME) on T cell function. The goal of this study was to determine whether T cells in tumor tissue were functionally impaired compared to T cells in non-tumor bowel (NTB) tissue from the same patients. We showed that T cell populations are affected differently by the TME. In the tumor, T cells produced more IL-17 and less IL-2 per cell than their counterparts from NTB tissue. T cells from tumor tissue also had impaired proliferative ability compared to T cells in NTB tissue. This impairment was not related to the frequency of IL-2 producing T cells or regulatory T cells, but T cells from the TME had a higher co-expression of inhibitory receptors than T cells from NTB. Overall, our data indicate that T cells in tumor tissue are functionally altered by the CRC TME, which is likely due to cell intrinsic factors. The TME is therefore an important consideration in predicting the effect of immune modulatory therapies.

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“…3,4 IFNg, in turn, provokes the adaptive upregulation of the programmed death ligand 1 (PD-L1, also known as B7-H1) on nearby tumor cells via NFkB, 5 thereby mediating a negative feedback mechanism that ultimately leads to T-cell exhaustion in tumor-infiltrating lymphocytes. Upon binding of PD-L1 to its programmed death receptor (PD-1) on T lymphocytes, it limits the activity of the T-cell receptor (TCR) and thereby abolishes cytolytic activity.…”

Section: Introductionmentioning

confidence: 99%

PD-L1 (CD274) promoter methylation predicts survival in colorectal cancer patients

et al. 2016

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This study evaluates promoter methylation of the programmed cell death ligand 1 (PD-L1) as a biomarker in a cohort of 383 colorectal cancer patients. PD-L1 methylation (mPD-L1) was inversely correlated with PD-L1 mRNA expression (p D 0.001) and was associated with significantly shorter overall survival (OS, p D 0.003) and recurrence-free survival (RFS, p < 0.001). In age-stratified multivariate Cox proportional hazards analyses including sex, tumor, nodal, distant metastasis categories, microsatellite instability (MSI)-status, and PD-L1 mRNA, mPD-L1 is classified as an independent prognostic factor (OS: p D 0.030; RFS: p < 0.001). Further studies are needed to evaluate PD-L1 methylation as a biomarker for response prediction of immunotherapies targeting the PD-1/PD-L1 axis.

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PD-1+ CD8+ T cells are exhausted in tumours and functional in draining lymph nodes of colorectal cancer patients

Cited by 97 publications

References 27 publications

Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer

Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer

Functional impairment of infiltrating T cells in human colorectal cancer

PD-L1 (CD274) promoter methylation predicts survival in colorectal cancer patients

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