Abstract
The tumor suppressor PTEN (Phosphatase and Tensin homolog deleted on Chromosome 10) executes critical biological functions that limit cellular growth and proliferation. PTEN inhibits activation of the proto-oncogenic PI3K pathway and is required during embryogenesis and to suppress tumor formation and cancer progression throughout life. The critical role that PTEN plays in restraining cellular growth has been validated through the generation of a number of animal models whereby PTEN inactivation invariably leads to tumor formation in a cell-autonomous fashion. However, the increasing understanding of the mechanisms through which the immune system contributes to suppressing tumor progression has highlighted how, in a cell non-autonomous fashion, cancer-associated mutations can indirectly enhance oncogenesis by evading immune cell recognition. Here, in light of the essential role of PTEN in the regulation of immune cell development and function, and based on recent findings showing that PTEN loss can promote resistance to immune checkpoint inhibitors in various tumor types, we re-evaluate our understanding of the mechanisms through which PTEN functions as a tumor suppressor and postulate that this task is achieved through a combination of cell autonomous and non-autonomous effects. We highlight some of the critical studies that have delineated the functional role of PTEN in immune cell development and blood malignancies and propose new strategies for the treatment of PTEN loss-driven diseases.
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Abbreviations
- ACT:
-
Adoptive T-cell therapy
- AKT:
-
Protein Kinase B (Xie and Weiskirchen 2020)
- AML:
-
Acute myeloid leukemia
- APC:
-
Antigen-presenting cells
- BCR:
-
B cell receptors
- BMDC:
-
Bone marrow-derived dendritic cells
- BTK:
-
Bruton’s tyrosine kinase
- CAC:
-
Colitis-associated colon cancer
- CCL2:
-
Chemokine (C–C motif) ligand 2
- cDC:
-
Conventional DCs
- COVID-19:
-
Coronavirus disease 2019
- CSR:
-
Class switch recombination
- CTLA4:
-
Cytotoxic T lymphocyte antigen 4
- DCs:
-
Dendritic cells
- ERK1/2:
-
Extracellular signal-regulated kinase 1/2
- FDA:
-
Food and Drug Administration
- GBM:
-
Glioblastoma multiforme
- GPCRs:
-
G-protein coupled receptors
- HECT:
-
Homologous to E6AP C-terminus
- HSC:
-
Hematopoietic stem cells
- I3C:
-
Indole-3-Carbinol
- ICOS:
-
Inducible T-cell COStimulator
- IFN:
-
Interferon
- IGFR:
-
Insulin-like Growth Factor Receptor
- IL-12:
-
Interleukin 12
- IR:
-
Insulin Receptor
- IRF3:
-
Interferon regulatory factor 3
- ITK:
-
Tyrosine-protein kinase ITK/TSK, a.k.a. interleukin-2-inducible T-cell kinase
- LCK:
-
Lymphocyte protein tyrosine kinase
- LOH:
-
Loss of heterozygosity
- LPS:
-
Lipopolysaccharide
- MAPK:
-
Mitogen-Activated Protein Kinase
- MEFs:
-
Mouse embryonic fibroblasts
- MHC:
-
Major histocompatibility complex
- mTORC1:
-
Mechanistic target of rapamycin complex 1
- mTORC2:
-
Mechanistic target of rapamycin complex 2
- NEDD4:
-
Neuronal precursor cell-expressed developmentally downregulated 4
- NK cells:
-
Natural killer cells
- PD1:
-
Programmed cell death protein 1
- PDGFR:
-
Platelet-Derived Growth Factor Receptor
- PD-L1:
-
Programmed death-ligand 1
- PD-L2:
-
Programmed death-ligand 2
- PH domain:
-
Pleckstrin homology (PH) domain
- PHTS:
-
PTEN Hamartoma Tumor Syndrome
- PI3K:
-
Phosphoinositide-3-kinases
- PIP3:
-
Phosphatidylinositol-(3,4,5)-trisphosphate
- PTEN:
-
Phosphatase and Tensin homolog deleted on Chromosome 10
- RTKs:
-
Receptor tyrosine kinases
- SARS-CoV-2:
-
Severe acute respiratory syndrome coronavirus 2
- TAA:
-
Tumor-associated antigens
- T-ALL:
-
T cell Acute Lymphoblastic Leukemia
- TH1 cells:
-
T helper 1 cells
- TLR:
-
Toll-like receptors
- TNF:
-
Tumor Necrosis Factor
- Tregs:
-
Regulatory T cells
- TSC:
-
Tuberous sclerosis complex
- VEGF:
-
Vascular endothelial growth factor
- VSV:
-
Vesicular stomatitis virus
- WWP1:
-
WW Domain Containing E3 Ubiquitin Protein Ligase 1
- WWP2:
-
WW Domain Containing E3 Ubiquitin Protein Ligase 2
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Funding
A.P. is supported by a Victorian Cancer Agency (VCA) Mid-Career Research Fellowship (MCRF20027). This work is supported in part by a grant from the PTEN Research Foundation to P.P.P. Figures were created with BioRender.
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Papa, A., Pandolfi, P.P. (2022). PTEN in Immunity. In: Dominguez-Villar, M. (eds) PI3K and AKT Isoforms in Immunity . Current Topics in Microbiology and Immunology, vol 436. Springer, Cham. https://doi.org/10.1007/978-3-031-06566-8_4
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