Small molecule inhibitors against PD-1/PD-L1 immune checkpoints and current methodologies for their development: a review

Liu, Chang; Seeram, Navindra P.; Ma, Hang

doi:10.1186/s12935-021-01946-4

Cited by 53 publications

(29 citation statements)

References 123 publications

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“…More recently, the strategy for immune checkpoints, PD-1 and PD-L1, has become an immune therapy with amazing survival benefit ( Liu C. et al, 2021 ). Unfortunately, the effectiveness of immune checkpoint therapy is limited because only a small number of patients respond to the therapy.…”

Section: Resultsmentioning

confidence: 99%

Construction and Validation of an Immune Cell Signature Score to Evaluate Prognosis and Therapeutic Efficacy in Hepatocellular Carcinoma

Jian

Liu

et al. 2021

Front. Genet.

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Background: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy with high morbidity and mortality worldwide. Tumor immune microenvironment (TIME) plays a pivotal role in the outcome and treatment of HCC. However, the effect of immune cell signatures (ICSs) representing the characteristics of TIME on the prognosis and therapeutic benefit of HCC patients remains to be further studied.Materials and methods: In total, the gene expression profiles of 1,447 HCC patients from several databases, i.e., The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium, and Gene Expression Omnibus, were obtained and applied. Based on a comprehensive collection of marker genes, 182 ICSs were evaluated by single sample gene set enrichment analysis. Then, by performing univariate and multivariate Cox analysis and random forest modeling, four significant signatures were selected to fit an immune cell signature score (ICSscore).Results: In this study, an ICSscore-based prognostic model was constructed to stratify HCC patients into high-risk and low-risk groups in the TCGA-LIHC cohort, which was successfully validated in two independent cohorts. Moreover, the ICSscore values were found to positively correlate with the current American Joint Committee on Cancer staging system, indicating that ICSscore could act as a comparable biomarker for HCC risk stratification. In addition, when setting the four ICSs and ICSscores as features, the classifiers can significantly distinguish treatment-responding and non-responding samples in HCC. Also, in melanoma and breast cancer, the unified ICSscore could verify samples with therapeutic benefits.Conclusion: Overall, we simplified the tedious ICS to develop the ICSscore, which can be applied successfully for prognostic stratification and therapeutic evaluation in HCC. This study provides an insight into the therapeutic predictive efficacy of prognostic ICS, and a novel ICSscore was constructed to allow future expanded application.

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Section: Resultsmentioning

confidence: 99%

Construction and Validation of an Immune Cell Signature Score to Evaluate Prognosis and Therapeutic Efficacy in Hepatocellular Carcinoma

Jian

Liu

et al. 2021

Front. Genet.

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“…The expression of PD-L1 on the surface of immune cells present at the margin of the invasion is also strongly correlated with a better response, particularly if this expression is associated with significant infiltration of CD8 + cells [ 35 , 36 ]. In their review, Liu et al summarize the biophysical and biochemical assays employed for the measurements of the binding capacities, molecular interactions, and blocking effects of small molecule inhibitors on the PD-1/PD-L1 system [ 37 ]. Among these small molecules, polyphenols could be good candidates.…”

Section: Polyphenols As Adjuvants To Enhance Anti-pd-1/anti-pd-l1 Immunotherapiesmentioning

confidence: 99%

PD-1/PD-L1 Checkpoints and Resveratrol: A Controversial New Way for a Therapeutic Strategy

Delmas

Hermetet

Aires

2021

Cancers

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Immune checkpoints refer to a range of immunoregulatory molecules that modulate the immune response. For example, proteins expressed at the surface of T-cells (including PD-1 and CTLA-4) and their ligands (PD-L1 and B7-1/B7-2, respectively), expressed by cancer cells and antigen-presenting cells, are needed to prevent excessive immune responses. However, they dampen anti-tumor immunity by limiting T-cell activity, making them promising therapeutic targets in cancer. Although immunotherapies using checkpoint blocking/neutralizing antibodies targeting PD-L1 or PD-1 have proven their superiority over conventional chemotherapies or targeted therapies by enhancing T-cell-mediated anti-tumor immunity, some limitations have emerged. These include a relatively low rate of “responders” (<50%; irrespective of cancer type), the high cost of injections, and a rare risk of hyper-progression. For clinicians, the current challenge is thus to improve the existing therapies, potentially through combinatory approaches. Polyphenols such as resveratrol (RSV), a trihydroxystilbene found in various plants and an adjuvant in numerous nutraceuticals, have been proposed as potential therapeutic targets. Beyond its well-known pleiotropic effects, RSV affects PD-L1 and PD-1 expression as well as PD-L1 subcellular localization and post-translational modifications, which we review here. We also summarize the consequences of PD-1/PD-L1 signaling, the modalities of their blockade in the context of cancer, and the current status and limitations of these immunotherapies. Finally, we discuss their potential use in combination with chemotherapies, and, using RSV as a model, we propose polyphenols as adjuvants to enhance the efficacy of anti-PD-1/anti-PD-L1 immunotherapies.

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“…With the discoveries of molecular mechanisms associated with thyroid cancer initiation and progression, a new generation of drugs has been designed to target these dysregulated pathways preferentially expressed in thyroid cancer. Several targeted anticancer agents have emerged as promising monotherapy options which include some of the recently evaluated small molecule inhibitors such as targeted inhibitors of tyrosine kinase, immune checkpoint (PDL-1), NOTCH1, and mTOR pathways [ 32 , 33 , 34 , 35 ]. New targeted therapies that can block the functions of molecules involved in the oncogenic transformation of indolent tumors to the aggressive ones are among the promising treatment modalities.…”

Section: Targeted Therapies In Thyroid Cancermentioning

confidence: 99%

Advances in Biomarker-Driven Targeted Therapies in Thyroid Cancer

Mishra

Laha

Grant

et al. 2021

Cancers

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Thyroid cancer is the most common type of endocrine malignancy comprising 2–3% of all cancers, with a constant rise in the incidence rate. The standard first-line treatments for thyroid cancer include surgery and radioactive iodine ablation, and a majority of patients show a good response to these therapies. Despite a better response and outcome, approximately twenty percent of patients develop disease recurrence and distant metastasis. With improved knowledge of molecular dysregulation and biological characteristics of thyroid cancer, the development of new treatment strategies comprising novel targets has accelerated. Biomarker-driven targeted therapies have now emerged as a trend for personalized treatments in patients with advanced cancers, and several multiple receptor kinase inhibitors have entered clinical trials (phase I/II/III) to evaluate their safety and efficacy. Most extensively investigated and clinically approved targeted therapies in thyroid cancer include the tyrosine receptor kinase inhibitors that target antiangiogenic markers, BRAF mutation, PI3K/AKT, and MAPK pathway components. In this review, we focus on the current advances in targeted mono- and combination therapies for various types of thyroid cancer.

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Small molecule inhibitors against PD-1/PD-L1 immune checkpoints and current methodologies for their development: a review

Cited by 53 publications

References 123 publications

Construction and Validation of an Immune Cell Signature Score to Evaluate Prognosis and Therapeutic Efficacy in Hepatocellular Carcinoma

Construction and Validation of an Immune Cell Signature Score to Evaluate Prognosis and Therapeutic Efficacy in Hepatocellular Carcinoma

PD-1/PD-L1 Checkpoints and Resveratrol: A Controversial New Way for a Therapeutic Strategy

Advances in Biomarker-Driven Targeted Therapies in Thyroid Cancer

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