Life Sciences Research for Lifelong Health

Klaus Okkenhaug

Research Summary

Our group focuses on how a group of enzymes called phosphoinositide 3-kinases (PI3Ks) are used by cells of the immune system to instruct and coordinate defences against pathogens. Cells of the immune system can express up to eight different forms of PI3K, which act as second messenger signalling molecules within cells that control diverse of cellular functions and genetic programmes.

Our group tries to dissect the unique roles played by individual forms of PI3K with particular focus on their roles in B cells and T cells. We also ask what the effect of inhibiting or enhancing the activity of individual forms of PI3K has on immunity to infections.

Most of our work to date has focused on PI3Kδ. The activation of PI3Kδ is one of the first events that happen inside a T cell or B cell when it first is exposed to a foreign antigen. Because PI3Kδ is expressed at very low levels in other organs in the body, it is thought that targeting PI3K with drugs may be an effective way to suppress immune responses without some of the side effects associated with many immunosuppressive drugs in current use.

We therefore work closely with colleagues in pharmaceutical companies who have developed specific inhibitors against PI3Kδ or other forms of PI3K to help predict and understand the effect of such drugs on the immune system.

Latest Publications

Targeting PI3K in Cancer: Impact on Tumor Cells, Their Protective Stroma, Angiogenesis, and Immunotherapy.
Okkenhaug K, Graupera M, Vanhaesebroeck B

The PI3K pathway is hyperactivated in most cancers, yet the capacity of PI3K inhibitors to induce tumor cell death is limited. The efficacy of PI3K inhibition can also derive from interference with the cancer cells' ability to respond to stromal signals, as illustrated by the approved PI3Kδ inhibitor idelalisib in B-cell malignancies. Inhibition of the leukocyte-enriched PI3Kδ or PI3Kγ may unleash antitumor T-cell responses by inhibiting regulatory T cells and immune-suppressive myeloid cells. Moreover, tumor angiogenesis may be targeted by PI3K inhibitors to enhance cancer therapy. Future work should therefore also explore the effects of PI3K inhibitors on the tumor stroma, in addition to their cancer cell-intrinsic impact.

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Cancer discovery, , 2159-8290, , 2016

PMID: 27655435

Ionic immune suppression within the tumour microenvironment limits T cell effector function.
Eil R, Vodnala SK, Clever D, Klebanoff CA, Sukumar M, Pan JH, Palmer DC, Gros A, Yamamoto TN, Patel SJ, Guittard GC, Yu Z, Carbonaro V, Okkenhaug K, Schrump DS, Linehan WM, Roychoudhuri R, Restifo NP

Tumours progress despite being infiltrated by tumour-specific effector T cells. Tumours contain areas of cellular necrosis, which are associated with poor survival in a variety of cancers. Here, we show that necrosis releases intracellular potassium ions into the extracellular fluid of mouse and human tumours, causing profound suppression of T cell effector function. Elevation of the extracellular potassium concentration ([K(+)]e) impairs T cell receptor (TCR)-driven Akt-mTOR phosphorylation and effector programmes. Potassium-mediated suppression of Akt-mTOR signalling and T cell function is dependent upon the activity of the serine/threonine phosphatase PP2A. Although the suppressive effect mediated by elevated [K(+)]e is independent of changes in plasma membrane potential (Vm), it requires an increase in intracellular potassium ([K(+)]i). Accordingly, augmenting potassium efflux in tumour-specific T cells by overexpressing the potassium channel Kv1.3 lowers [K(+)]i and improves effector functions in vitro and in vivo and enhances tumour clearance and survival in melanoma-bearing mice. These results uncover an ionic checkpoint that blocks T cell function in tumours and identify potential new strategies for cancer immunotherapy.

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Nature, 537, 1476-4687, 539-543, 2016

PMID: 27626381

PI3Kδ and primary immunodeficiencies.
Lucas CL, Chandra A, Nejentsev S, Condliffe AM, Okkenhaug K

Primary immunodeficiencies are inherited disorders of the immune system, often caused by the mutation of genes required for lymphocyte development and activation. Recently, several studies have identified gain-of-function mutations in the phosphoinositide 3-kinase (PI3K) genes PIK3CD (which encodes p110δ) and PIK3R1 (which encodes p85α) that cause a combined immunodeficiency syndrome, referred to as activated PI3Kδ syndrome (APDS; also known as p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency (PASLI)). Paradoxically, both loss-of-function and gain-of-function mutations that affect these genes lead to immunosuppression, albeit via different mechanisms. Here, we review the roles of PI3Kδ in adaptive immunity, describe the clinical manifestations and mechanisms of disease in APDS and highlight new insights into PI3Kδ gleaned from these patients, as well as implications of these findings for clinical therapy.

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Nature reviews. Immunology, , 1474-1741, , 2016

PMID: 27616589

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Latest Publications

Targeting PI3K in Cancer: Impact on Tumor Cells, Their Protective Stroma, Angiogenesis, and Immunotherapy.

Okkenhaug K, Graupera M, Vanhaesebroeck B

Cancer discovery
2159-8290: (2016)

PMID: 27655435

Ionic immune suppression within the tumour microenvironment limits T cell effector function.

Eil R, Vodnala SK, Clever D

Nature
537 1476-4687:539-543 (2016)

PMID: 27626381

PI3Kδ and primary immunodeficiencies.

Lucas CL, Chandra A, Nejentsev S

Nature reviews. Immunology
1474-1741: (2016)

PMID: 27616589

Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study.

Coulter TI, Chandra A, Bacon CM

The Journal of allergy and clinical immunology
1097-6825: (2016)

PMID: 27555459

BACH2 regulates CD8(+) T cell differentiation by controlling access of AP-1 factors to enhancers.

Roychoudhuri R, Clever D, Li P

Nature immunology
1529-2916: (2016)

PMID: 27158840

The transcription factor BACH2 promotes tumor immunosuppression.

Roychoudhuri R, Eil RL, Clever D

The Journal of clinical investigation
1558-8238: (2016)

PMID: 26731475

Oncogenic PI3Kα promotes multipotency in breast epithelial cells.

Okkenhaug K, Roychoudhuri R

Science signaling
8 1937-9145:pe3 (2015)

PMID: 26535006

PI3K Signaling in Normal B Cells and Chronic Lymphocytic Leukemia (CLL).

Okkenhaug K, Burger JA

Current topics in microbiology and immunology
393 0070-217X:123-42 (2016)

PMID: 26350103

Editorial: Lipid Signaling in T Cell Development and Function.

Sauer K, Okkenhaug K

Frontiers in immunology
6 1664-3224:410 (2015)

PMID: 26322043

PI3Kδ Regulates the Magnitude of CD8+ T Cell Responses after Challenge with Listeria monocytogenes.

Pearce VQ, Bouabe H, MacQueen AR

Journal of immunology (Baltimore, Md. : 1950)
1550-6606: (2015)

PMID: 26311905