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Review
. 2020 Dec 4;8(4):735.
doi: 10.3390/vaccines8040735.

Transcriptional Regulation of Cancer Immune Checkpoints: Emerging Strategies for Immunotherapy

Simran Venkatraman  1 , Jarek Meller  2   3 , Suradej Hongeng  4 , Rutaiwan Tohtong  1   5 , Somchai Chutipongtanate  6   7
Affiliations
Review

Transcriptional Regulation of Cancer Immune Checkpoints: Emerging Strategies for Immunotherapy

Simran Venkatraman et al. Vaccines (Basel). .

Abstract

The study of immune evasion has gained a well-deserved eminence in cancer research by successfully developing a new class of therapeutics, immune checkpoint inhibitors, such as pembrolizumab and nivolumab, anti-PD-1 antibodies. By aiming at the immune checkpoint blockade (ICB), these new therapeutics have advanced cancer treatment with notable increases in overall survival and tumor remission. However, recent reports reveal that 40-60% of patients fail to benefit from ICB therapy due to acquired resistance or tumor relapse. This resistance may stem from increased expression of co-inhibitory immune checkpoints or alterations in the tumor microenvironment that promotes immune suppression. Because these mechanisms are poorly elucidated, the transcription factors that regulate immune checkpoints, known as "master regulators", have garnered interest. These include AP-1, IRF-1, MYC, and STAT3, which are known to regulate PD/PD-L1 and CTLA-4. Identifying these and other potential master regulators as putative therapeutic targets or biomarkers can be facilitated by mining cancer literature, public datasets, and cancer genomics resources. In this review, we describe recent advances in master regulator identification and characterization of the mechanisms underlying immune checkpoints regulation, and discuss how these master regulators of immune checkpoint molecular expression can be targeted as a form of auxiliary therapeutic strategy to complement traditional immunotherapy.

Keywords: cancer immune response; immune checkpoint inhibitor; transcription factors; tumor microenvironment.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Roles of STAT3 master regulators in cancer immunity. In the context of oncoimmunology (top panel), STAT3 phosphorylation in cancer cells leads to multiple interactions between immune cells in the tumor microenvironment to promote tumor growth, angiogenesis, and metastasis. In the context of immune checkpoint regulation (lower panel), STAT3 transcription factor binds to the promoter of the co-inhibitory immune checkpoint molecule PD-L1, thereby regulates its expression and downstream effects.
See this image and copyright information in PMC

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