PTEN at the interface of immune tolerance and tumor suppression

doi:10.1007/s11515-017-1443-5

Front. Biol.

2017, Vol. 12

Issue (3) : 163-174 https://doi.org/10.1007/s11515-017-1443-5

REVIEW

PTEN at the interface of immune tolerance and tumor suppression

Andrew Brandmaier, Sheng-Qi Hou, Sandra Demaria, Silvia C. Formenti, Wen H. Shen(

)

Department of Radiation Oncology, Weill Cornell Medicine, Cornell University, New York, NY 10065, USA

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Abstract

BACKGROUND: PTEN is well known to function as a tumor suppressor that antagonizes oncogenic signaling and maintains genomic stability. ThePTEN gene is frequently deleted or mutated in human cancers and the wide cancer spectrum associated with PTEN deficiency has been recapitulated in a variety of mouse models ofPten deletion or mutation. Pten mutations are highly penetrant in causing various types of spontaneous tumors that often exhibit resistance to anticancer therapies including immunotherapy. Recent studies demonstrate that PTEN also regulates immune functionality.

OBJECTIVE: To understand the multifaceted functions of PTEN as both a tumor suppressor and an immune regulator.

METHODS: This review will summarize the emerging knowledge of PTEN function in cancer immunoediting. In addition, the mechanisms underlying functional integration of various PTEN pathways in regulating cancer evolution and tumor immunity will be highlighted.

RESULTS: Recent preclinical and clinical studies revealed the essential role of PTEN in maintaining immune homeostasis, which significantly expands the repertoire of PTEN functions. Mechanistically, aberrant PTEN signaling alters the interplay between the immune system and tumors, leading to immunosuppression and tumor escape.

CONCLUSION: Rational design of personalized anti-cancer treatment requires mechanistic understanding of diverse PTEN signaling pathways in modulation of the crosstalk between tumor and immune cells.

Keywords PTEN phosphoinositide 3-kinase regulatory T cells genome epigenome metabolism

Corresponding Author(s): Wen H. Shen

Just Accepted Date: 09 February 2017 Online First Date: 20 March 2017 Issue Date: 19 June 2017

Cite this article:

Andrew Brandmaier,Sheng-Qi Hou,Sandra Demaria, et al. PTEN at the interface of immune tolerance and tumor suppression[J]. Front. Biol., 2017, 12(3): 163-174.

URL:

https://academic.hep.com.cn/fib/EN/10.1007/s11515-017-1443-5
https://academic.hep.com.cn/fib/EN/Y2017/V12/I3/163

Tab.1 Immune-specific Pten deletion and corresponding phenotypes

Fig.1 PTEN signaling in T_reg cells. The canonical PTEN-PI3K-AKT signaling pathway plays a central role in maintaining the identity of T_reg cells and their lineage stability. PTEN antagonizes PI3K-mediated generation of the second messenger, PIP3, and subsequent AKT phosphorylation. Upon TCR engagement, activated AKT phosphorylates FOXO proteins (such as FOXO1) and prevents them from entering the nucleus. Nuclear exclusion of FOXO proteins abrogates their transcriptional activity as a partner for FOXP3, leading to T_reg instability. Checkpoint molecules that mediate the PD-1-CK2-PTEN pathway and the NRP1-PTEN pathway help maintain the level of PTEN in T_regs. The PD-1 suppressive signal reduces the expression of CK2, which prevents CK2-mediated PTEN degradation. NRP1 is highly expressed on natural T_reg cells. Upon interaction of NRP1 with its ligand, semaphorin-A, PTEN is recruited to the immunological synapse to antagonize PI3K and promote T_reg stability.

Fig.2 PTEN acts as a guardian of the genome, epigenome and metabolome to maintain cellular homeostasis. PTEN functions in both the cytoplasm and the nucleus to control multiple fundamental machineries for tumor suppression. PTEN regulates fatty acid oxidation, glycolysis and glutaminolysis in both PI3K–dependent and –independent manners. PTEN also functions in the nucleus to regulate multiple processes of genetic transmission during the cell cycle. When PTEN is mutated or inactivated, cells exhibit DNA replication and chromosome segregation defects, as well as structural aberrations such as centromere breakage, DSBs, chromosome entanglement, aneuploidy and polyploidy. Moreover, PTEN maintains proper chromatin organization through epigenetic regulation of histone modification.

Fig.3 The Yin and Yang of PTEN-mediated cancer immunoediting: implication for targeted anti-tumor therapy. Alterations of PTEN and its signaling significantly affect immune regulation and the process of malignant transformation. PTEN is frequently mutated or inactivated during cancer evolution. Loss of PTEN leads to activation of multiple tumor-intrinsic oncogenic signals that can serve as therapeutic targets for anti-cancer treatment. On the other hand, PTEN inactivation disrupts immune tolerance and can enhance anti-tumor immunity. A thorough understanding of both the Yin and Yang of PTEN function at the immunological synapse is required to achieve the dual goal of promoting PTEN activity in tumors and suppressing PTEN signaling in regulatory immune cells.

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