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PTEN in Immunity

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PI3K and AKT Isoforms in Immunity

Part of the book series: Current Topics in Microbiology and Immunology ((CT MICROBIOLOGY,volume 436))

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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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Authors and Affiliations

  1. Cancer Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, 3800, Australia

    Antonella Papa

  2. Renown Cancer Institute, Nevada System of Higher Education, Reno, NV, USA

    Pier Paolo Pandolfi

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  1. Antonella Papa
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  2. Pier Paolo Pandolfi
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Correspondence to Antonella Papa or Pier Paolo Pandolfi .

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  1. Faculty of Medicine, Imperial College London, London, UK

    Margarita Dominguez-Villar

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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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