Cancer Immunotherapy: A Focus on the Regulation of Immune Checkpoints

Shi, Tao; Ma, Yanyu; Yu, Lingfeng; Jiang, Jiaxuan; Shen, Shihao; Hou, Yinglong; Wang, Tingting

doi:10.3390/ijms19051389

Cited by 88 publications

(65 citation statements)

References 86 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The omics-era of cancer research has brought a wealth of information regarding molecular details of cancer cells, the different types of cancer cells, the differences in the cause of the disease, and has also revealed new drug targets [3,4]. There is now much potential for personalized treatment especially in the field of immunotherapeutics [5][6][7], which seek to bolster the body's natural immune defense mechanism against aberrant cells.…”

Section: Introductionmentioning

confidence: 99%

Iron and Copper Intracellular Chelation as an Anticancer Drug Strategy

et al. 2018

View full text Add to dashboard Cite

A very promising direction in the development of anticancer drugs is inhibiting the molecular pathways that keep cancer cells alive and able to metastasize. Copper and iron are two essential metals that play significant roles in the rapid proliferation of cancer cells and several chelators have been studied to suppress the bioavailability of these metals in the cells. This review discusses the major contributions that Cu and Fe play in the progression and spreading of cancer and evaluates select Cu and Fe chelators that demonstrate great promise as anticancer drugs. Efforts to improve the cellular delivery, efficacy, and tumor responsiveness of these chelators are also presented including a transmetallation strategy for dual targeting of Cu and Fe. To elucidate the effectiveness and specificity of Cu and Fe chelators for treating cancer, analytical tools are described for measuring Cu and Fe levels and for tracking the metals in cells, tissue, and the body.

show abstract

Section: Introductionmentioning

confidence: 99%

Iron and Copper Intracellular Chelation as an Anticancer Drug Strategy

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Unlike CTLA-4, CD28-B7 interaction stimulates T cell activation. 5,8 Furthermore, T cell exhaustion induces the expression of multiple co-inhibitory receptors such as LAG-3, TIM-3 and PD-1. Additionally, TIGIT and VISTA are emerging co-inhibitory immune checkpoints.…”

Section: Introductionmentioning

confidence: 99%

“…Reports show that both TIGIT and VISTA stimulates an inhibitory signal to suppress T cell activation, promoting an immunosuppressive environment. 8,9 Epigenetic alterations/modulations of immune checkpoints such as aberrant methylation/demethylation pattern results in altered gene expression and tumorigenesis. It has been reported that methylation of the 5th cytosine residue of the CpGs in the promoter regions of genes are associated with their suppression.…”

Section: Introductionmentioning

confidence: 99%

DNA methylation of immune checkpoints in the peripheral blood of breast and colorectal cancer patients

et al. 2018

View full text Add to dashboard Cite

Aberrant expression of immune checkpoints (ICs) in cancer creates an immunosuppressive microenvironment, which supports immune evasion of tumor cells. We have recently reported that epigenetic modifications are critical for ICs expression in the tumor microenvironment (TME) of primary breast cancer (PBC) and colorectal cancer (CRC). Herein, we investigated transcriptomic expression of ICs (PD-1, CTLA-4, LAG-3, TIM-3, TIGIT) and PD-L1 in peripheral blood of PBC and CRC patients, compared to healthy donors (HD). We found that expressions of TIM-3, TIGIT, PD-L1 were significantly upregulated, while LAG-3 expression was downregulated in peripheral blood of PBC and CRC patients. Demethylation enzymes TET2 and TET3 were also upregulated. In addition, promoter DNA methylation status of PD-1 was significantly hypermethylated, while PD-L1 was hypomethylated in PBC and CRC patients. Furthermore, TIGIT was significantly hypomethylated only in CRC patients. Remarkably, promoter methylation status of LAG-3, TIGIT and PD-L1 was in concordance with transcriptomic expression in CRC: the more the hypomethylation, the higher the expression. In comparison, we found that CTLA-4, TIM-3, TIGIT and PD-L1 in PBC, and CTLA-4 in CRC patients were significantly upregulated in peripheral blood, compared with tumor tissues of the same patients. However, demethylation status of all ICs was higher in TT, except for TIGIT in PBC, and CTLA-4 in CRC patients. These data indicate that the underlying mechanisms behind peripheral upregulation of PD-L1 and TIGIT in cancer patients could be due to aberrant promoter methylation profile. Moreover, demethylation inhibitors together with anti-PD-L1/ anti-TIGIT could be a more efficient therapeutic strategy in cancer patients. ARTICLE HISTORY

show abstract

“…In recent years, accumulating evidence has highlighted the role of immunity in patient response to anticancer agents. [29,30]Our results demonstrated that the PARP inhibitor exhibited low levels of tumor inhibition effects on OSCC, which may be due to the induction of HR-mediated DNA damage response. However, the role of PARP inhibition in cancer-associated immunity has been largely unknown.…”

Section: Discussionmentioning

confidence: 94%

Repression of BET activity sensitizes oral squamous cell carcinoma to PARP inhibition via inhibiting DNA homologous recombination and immune inhibition

Liu

Zhang

2020

Preprint

View full text Add to dashboard Cite

Background: To investigate the root cause of therapeutic resistance underlying oral squamous cell carcinoma (OSCC) to the PARP inhibitor olaparib and explore the combination with the BET inhibitor JQ1 to augment its treatment effects.Material and Methods: Cell viability were detected in the study. We also evaluated the expression of a series of factors through quantitative real-time PCR, immunofluorescence and western blot. The effect of combining JQ1 and olaparib in xenograft OSCC mouse model was also examined.Results: The sensitivity of Cal27 cells to olaparib was better than Scc25. Functional assays demonstrated that olaparib induced HR repair and upregulated PD-L1 expression, which results in drug resistance of OSCC to olaparib. Variations of these factors in the two cell lines may explain different sensitivity to olaparib. Moreover, the JQ1 BET inhibitor and olaparib synergistically exhibited anti-cancer effects in OSCC in vitro and in vivo and inhibited essential HR repair factors RAD51, BRCA1, and TOPBP1 through the ATR/CHK1 pathway and immune suppression mediated by the PD-L1 pathway.Conclusions: Elevated HR and PD-L1 are involved in resistance mechanisms of OSCC to olaparib, attenuating its anti-tumor effects. Our results suggest that the strong synergistic anti-cancer activity of combining olaparib with BET inhibitor in OSCC may be via suppression of the ATR/CHK1-mediated DNA damage response and PD-L1-related immune escape, indicating this combination strategy as a possible therapy in OSCC.

show abstract

Cancer Immunotherapy: A Focus on the Regulation of Immune Checkpoints

Cited by 88 publications

References 86 publications

Iron and Copper Intracellular Chelation as an Anticancer Drug Strategy

Iron and Copper Intracellular Chelation as an Anticancer Drug Strategy

DNA methylation of immune checkpoints in the peripheral blood of breast and colorectal cancer patients

Repression of BET activity sensitizes oral squamous cell carcinoma to PARP inhibition via inhibiting DNA homologous recombination and immune inhibition

Contact Info

Product

Resources

About