Assessment of the expression of the immune checkpoint molecules PD‐1, CTLA4, TIM‐3 and LAG‐3 across different cancers in relation to treatment response, tumor‐infiltrating immune cells and survival

Tu, Lei; Guan, Renguo; Yang, Hanting; Zhou, Yu; Hong, Wang; Ma, Lulu; Zhao, Guangzhe; Yu, Min

doi:10.1002/ijc.32785

Cited by 129 publications

(115 citation statements)

References 38 publications

(71 reference statements)

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“…Back to the question posed at the beginning of this section, LAG3 expression was found to be associated with poor clinicopathological factors and eliciting immune suppressive function, supporting the hypothesis that the expression of LAG3 in breast cancer patients should lead to poor survival. However, inconsistent with the present results, the ndings of several previous studies indicated a favorable association between high expression of LAG3 and cancer-speci c survival, especially in ER-, HER2 + and basal-like subtypes (47,66,67). Interestingly, another published study found that serum LAG3 had a close correlation with prolonged survival in ER + patients (42).…”

Section: Discussioncontrasting

confidence: 99%

Molecular and Clinical Characterization of LAG3 in Breast Cancer Through 2994 Samples

Liu

Zhai

et al. 2020

Preprint

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Background Despite the promising impact of cancer immunotherapy targeting CTLA4 and PD1/PDL1, a large number of cancer patients fail to respond. LAG3 (Lymphocyte Activating 3), also named CD233, is a protein Coding gene served as alternative inhibitory receptors to be targeted in the clinic. The impact of LAG3 on immune cell populations and co-regulation of immune response in breast cancer remained largely unknown. Methods To characterize the role of LAG3 in breast cancer, we investigated transcriptome data and associated clinical information derived from a total of 2994 breast cancer patients. Results We observed that LAG3 was closely correlated with major molecular and clinical characteristics, and was more likely to be enriched in higher malignant subtype, suggesting LAG3 was a potential biomarker of triple-negative breast cancer. Furthermore, we estimated the landscape of relationship between LAG3 and ten types of cell populations in breast cancer. Gene ontology analysis revealed LAG3 were strongly correlated with immune response and inflammatory activities. We investigated the correlation pattern between LAG3 and immune modulators in pan-cancer, especially the synergistic role of LAG3 with other immune checkpoints members in breast cancer. Conclusions LAG3 expression was closely related to malignancy of breast cancer and might serve as a potential biomarker; LAG3 might plays an important role in regulating tumor immune microenvironment, not only T cells, but also other immune cells. More importantly, LAG3 might synergize with CTLA4, PD1/ PDL1 and other immune checkpoints, thereby lending more evidences to combination cancer immunotherapy by targeting LAG3, PD1/PDL1, and CTLA4 together.

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Section: Discussioncontrasting

confidence: 99%

Molecular and Clinical Characterization of LAG3 in Breast Cancer Through 2994 Samples

Liu

Zhai

et al. 2020

Preprint

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“…Immune checkpoints commonly play significant roles in triggering the cancer immunity escape by mediating the interaction between tumor cells and TIICs, so their expressions were commonly positively correlated with TIICs abundance [32,33]. In our research, we found that the high infiltration of TIICs predicted worse outcomes in total LGG patients.…”

Section: Discussionsupporting

confidence: 49%

Characterization of clinical significance of PD-1/PD-Ls expression and methylation in patients with low grade glioma

Mei

Cai

et al. 2020

Preprint

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Background: Immune checkpoints play crucial roles in immune escape of cancer cells. However, the exact prognostic values of expression and methylation of programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1) and PD-L2 in low-grade glioma (LGG) have not been defined yet. Methods:A total of 514 LGG samples from TCGA dataset containing both PD-1, PD-L1 and PD-L2 expression, DNA methylation, and survival data were enrolled into our study. The clinical significance of PD-1/PD-Ls expression and methylation inLGG were explored. Besides, the correlation between PD-1/PD-Ls expression and methylation with the infiltration levels of tumor-infiltrating immune cells (TIICs) was assessed. Moreover, GO enticement analysis of PD-1/PD-Ls co-expressed genes was performed as well. R 3.6.2 and GraphPad Prism 8 were applied as main tools for the statistical analysis and graphical exhibition.Results: PD-1/PD-Ls had distinct co-expression patterns in LGG tissues. The expression and methylation status of PD-1/PD-Ls seemed to be various in differentLGG subtypes. Besides, upregulated PD-1/PD-Ls expression and hypo-methylation of PD-1/PD-Ls were associated with worse survival in LGG patients. In addition, PD-1/PD-Ls expression was revealed to be positively associated with TIICs infiltration, while their methylation was negatively associated with TIICs infiltration.Moreover, the PD-1/PDLs correlated gene profiles screening and Gene Ontology (GO) enrichment analysis uncovered that PD-1/PDLs and their positively correlated gene mainly participated in immune response related biological processes. Conclusions:High expression and hypo-methylation of PD-1/PD-Ls significantly correlated with unfavorable survival in LGG patients, suggesting LGG patients may benefit from PD1/PD-Ls checkpoint inhibitors treatment.

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“…Besides HLA-G and ILT-2, additional IC molecules such as programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated protein (CTLA-4), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), and CD95 are associated in tumor-driven immune escape mechanisms acting locally at the tumor site or systemically in the peripheral blood (24)(25)(26). The continuous upregulation and co-expression of multiple IC, being often observed in cancer and chronic infections, are indicative for an immunosuppressive/exhausted phenotype of T cells and are associated with loss of effector functions and immunosurveillance (27,28).…”

Section: Introductionmentioning

confidence: 99%

Soluble HLA-G and HLA-G Bearing Extracellular Vesicles Affect ILT-2 Positive and ILT-2 Negative CD8 T Cells Complementary

et al. 2020

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Tumor immune escape is associated with both, the expression of immune checkpoint molecules on peripheral immune cells and soluble forms of the human leukocyte antigen-G (HLA-G) in the blood, which are consequently discussed as clinical biomarker for disease status and outcome of cancer patients. HLA-G preferentially interacts with the inhibitory receptor immunoglobulin-like transcript (ILT) receptor-2 in the blood and can be secreted as free soluble molecules (sHLA-G) or via extracellular vesicles (EV). To investigate the contribution of these two forms to the expression of checkpoint molecules in peripheral blood, we primed peripheral blood mononuclear cells with purified soluble sHLA-G1 protein, or EV preparations derived from SUM149 cells transfected with membrane-bound HLA-G1 or control vector prior to anti-CD3/CD28 T cell activation. Our study demonstrated that priming of PBMC with sHLA-G1 protein prior to 48 h activation resulted in enhanced frequencies of ILT-2 expressing CD8 + T cells, and in an upregulation of immune checkpoint molecules CTLA-4, PD-1, TIM-3, and CD95 exclusively on ILT-2 positive CD8 + T cells. In contrast, when PBMC were primed with EV (containing HLA-G1 or not) upregulation of CTLA-4, PD-1, TIM-3, and CD95 occurred exclusively on ILT-2 negative CD8 + T cells. Taken together, our data suggest that priming with sHLA-G forms induces a pronounced immunosuppressive/exhausted phenotype and that priming with sHLA-G1 protein or EV derived from HLA-G1 positive or negative SUM149 cells affects CD8 + T cells complementary by targeting either the ILT-2 positive or negative subpopulation, respectively, after T cell activation.

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Assessment of the expression of the immune checkpoint molecules PD‐1, CTLA4, TIM‐3 and LAG‐3 across different cancers in relation to treatment response, tumor‐infiltrating immune cells and survival

Cited by 129 publications

References 38 publications

Molecular and Clinical Characterization of LAG3 in Breast Cancer Through 2994 Samples

Molecular and Clinical Characterization of LAG3 in Breast Cancer Through 2994 Samples

Characterization of clinical significance of PD-1/PD-Ls expression and methylation in patients with low grade glioma

Soluble HLA-G and HLA-G Bearing Extracellular Vesicles Affect ILT-2 Positive and ILT-2 Negative CD8 T Cells Complementary

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