Emerging role of PTEN loss in evasion of the immune response to tumours

Abstract

Mutations in PTEN activate the phosphoinositide 3-kinase (PI3K) signalling network, leading to many of the characteristic phenotypic changes of cancer. However, the primary effects of this gene on oncogenesis through control of the PI3K–AKT–mammalian target of rapamycin (mTOR) pathway might not be the only avenue by which PTEN affects tumour progression. PTEN has been shown to regulate the antiviral interferon network and thus alter how cancer cells communicate with and are targeted by immune cells. An active, T cell-infiltrated microenvironment is critical for immunotherapy success, which is also influenced by mutations in DNA damage repair pathways and the overall mutational burden of the tumour. As PTEN has a role in the maintenance of genomic integrity, it is likely that a loss of PTEN affects the immune response at two different levels and might therefore be instrumental in mediating failed responses to immunotherapy. In this review, we summarise findings that demonstrate how the loss of PTEN function elicits specific changes in the immune response in several types of cancer. We also discuss ongoing clinical trials that illustrate the potential utility of PTEN as a predictive biomarker for immune checkpoint blockade therapies.

Apremilast Regulates the Teff/Treg Balance to Ameliorate Uveitis via PI3K/AKT/FoxO1 Signaling Pathway

“…PI3Ks are a family of heterodimeric lipid kinases and can be divided into three classes based on different stimuli (43,44). AKT is one kind of serine protein kinase from the protein kinase AGC subfamily and acts as one of essential downstream factors of PI3K (44,45). PI3K/AKT is widely regarded as an important pathway to trigger several biochemical reactions that are closely related to metabolism and disease occurrence (46).…”

Transcriptional landscape of PTEN loss in primary prostate cancer

“…Accordingly, disruption of PTEN expression has previously been reported to lead to decreased innate immune response (73). Conversely, it has also been hypothesized that the increased genomic instability caused by, or associated with, PTEN loss can increase immunogenicity in the tumor micro-enviroment (TME) (74). This finding is of particular interest given that immune-responsive tumors can be good candidates for immunotherapy-based approaches.…”

PTEN Alterations and Their Role in Cancer Management: Are We Making Headway on Precision Medicine?

“…Given that RAD51 is a key component of the double-strand breaks (DSB) homologous recombination (HR) DNA repair systems, PTEN is currently viewed as a DNA-damage response regulator [32,33]. Importantly, PTEN loss may lead to DSB also through increased Akt-mediated cytoplasmic sequestration of the checkpoint kinase 1 (CHK1), resulting in altered G2/S arrest in response to DNA damage [34]. In addition, PTEN plays a key role in regulating and maintaining the integrity of several checkpoints during the G1-S and G2-M cell cycle transitions [35,36].…”

“…In B-cells, this negative regulation influences the proliferation, activation, and survival [55]. Given these considerations, it is not surprising that loss of PTEN activity is associated with cellular and humoral immune dysfunction and autoimmunity [9,34]. The cancer secretome, which is composed of macromolecules secreted by tumor cells, may stimulate the expression of immunosuppressive cytokines (e.g., IL-6 and IL-10) [57].…”