Abstract
The recent approval of immune checkpoint inhibitors drastically changed the standard treatments in many advanced cancer patients, but molecular changes within the tumor can prevent the activity of immunotherapy drugs. Thus, the introduction of the inhibitors of the immune checkpoint programmed death-1/programmed death ligand-1 (PD-1/PD-L1), should prompt deeper studies on resistance mechanisms, which can be caused by oncogenic mutations detected in cancer cells. PTEN, a tumor suppressor gene, dephosphorylates the lipid signaling intermediate PIP3 with inhibition of AKT activity, one of the main effectors of the PI3K signaling axis. As a consequence of genetic or epigenetic aberrations, PTEN expression is often altered, with increased activation of PI3K axis. Interestingly, some data confirmed that loss of PTEN expression modified the pattern of cytokine secretion creating an immune-suppressive microenvironment with increase of immune cell populations that can promote tumor progression. Moreover, PTEN loss may be ascribed to reduction of tumor infiltrating lymphocytes (TILs), which can explain the absence of activity of immune checkpoint inhibitors. This review describes the role of PTEN loss as a mechanism responsible for resistance to anti PD-1/PD-L1 treatment. Moreover, combinatorial strategies between PD-1/PD-L1 inhibitors and PI3K/AKT targeting drugs are proposed as a new strategy to overcome resistance to immune checkpoint inhibition.
Highlights
Accumulating evidence suggests that agents targeting immune checkpoints produce clinical benefit, including prolonged response and survival
The 30% of melanoma patients with phosphatase and homolog deleted from chromosome (PTEN) loss often presented a V600E BRAF point mutation [64,65]. The presence of both alterations is responsible for development of metastatic lesions in a mouse model [51] and the inhibition of both signaling (BRAF and phosphatidylinositol 3-kinase (PI3K)/AKT) caused a regression of melanoma, but upon arrest of drug administration, melanoma restart to grow indicating the presence of long-lived initiating cells
In this context PTEN abrogation could identify a different subset of melanoma patients: recently, it has been reported that PTEN loss promotes resistance to immunotherapy in a melanoma preclinical model [66] (Figure 1B)
Summary
Accumulating evidence suggests that agents targeting immune checkpoints produce clinical benefit, including prolonged response and survival. PI3K-AKT-mTOR pathway is negative regulators aiming at preventing an aberrant activation. Since PTEN is involved in theincontrol of a domain containing a PEST (Pro, Ser, Thr) sequence is involved the control wide range of processes including tumor growth and spread, metabolism, senescence and epithelial to of a wide range of processes including tumor growth and spread, metabolism, senescence and mesenchymal (EMT), its downregulation a pivotal role in thea progression many epithelial to transition mesenchymal transition (EMT), its plays downregulation plays pivotal roleof in the types of cancer. The abrogation of PTEN function induces the activation of 4EBP1 and p70S6 kinase, involved in the protein synthesis glucose transporter 4 (GLUT4) protein at the plasma membrane [13]. The abrogation of PTEN function induces the activation of 4EBP1 and p70S6 kinase, involved in the protein synthesis processes [14]. Cellular senescence is an irreversible growth arrest process mainly controlled by p53, p21, and p16ink4a proteins [17], and as reported for prostate cancer [18], PTEN loss can trigger cellular senescence both in vitro and in vivo
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