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.
Highlights
Cancer is a multi-faceted disease that while complex to treat possesses multiple vulnerabilities which can be targeted therapeutically
There has been a rapid development of immunotherapy strategies; for example, synthetically derived chimeric antigen receptor (CAR) T cells which recognize and direct specific cytotoxicity to target cells, recombinant cancer vaccines that prompt the immune response against tumors, and immune checkpoint blockade (ICB) therapy which inhibits cancer immune evasion [1]
Further investigations should be driven towards finding ways to either mitigate the immune-related adverse events (irAEs) with ICB therapy or devising a new therapeutic strategy that lowers the risk of developing adverse events
Summary
Cancer is a multi-faceted disease that while complex to treat possesses multiple vulnerabilities which can be targeted therapeutically. Acquired resistance may result from genetic instability due to DNA repair alterations, higher mutational burden, neoantigen load, copy number loss of tumor suppressor genes, or upregulation of alternate co-inhibitory ICs [15] This is reflected in a study showing a loss of PTEN promotes resistance to anti-PD-1 therapy in metastatic uterine leiomyosarcoma [16]. Much of current research is focused on either downstream effectors or upstream regulators (considered as “master regulators”) to modulate response to drug treatment as a promising avenue to overcome the resistance This concept has been successfully applied to identify ERK and FOXM1 as master regulators of cell fate and proliferation, respectively [17,18]. This article can be considered as a narrative review and the scientific rigor of the master regulator targeting strategies should be validated in the future
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