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Department of Pathology

 

PI3K in immunity, infection and cancer

Our group focuses on how a group of enzymes called phosphoinositide 3-kinases (PI3Ks) which 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, each of which can generate second messenger signalling molecules within cells that control diverse of cellular functions and genetic programmes.

We aim 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 and cancer.

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, t 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.

 

 

Group members: 

 

Postdocs:

PhD students:

 

Biography

Klaus Okkenhaug is Professor of Immunology in the Department of Pathology. He obtained his BSc. in Biochemistry from the University of Victoria, British Columbia, Canada, followed by a PhD. in Immunology from the University of Toronto, where he studied CD28 signalling in Robert Rottapel's lab. In 1999, he moved to London, UK, where he joined Bart Vanhaesebroeck's group at the Ludwig Institute for Cancer Research as a Postdoctoral Fellow, working on the role of the PI3Kδ in immune responses. There he generated the PI3Kδ kinase-dead knock-in mouse, which showed a key role for this PI3K isoform in B cell and T cells. Klaus was a group leader at the Babraham Institute from 2003-2017. Klaus has authored more than 100 per-reviewed publications and has made major contributions to the understanding of the roles of PI3K in immunity, infection and cancer. He has also advised several pharmaceutical companies on the development of specific PI3K inhibitors, some of which are now in use clinically.

Publications

Key publications: 

Selected recent primary research papers:

PI3Kδ Forms Distinct Multiprotein Complexes at the TCR Signalosome in Naïve and Differentiated CD4 + T Cells

Luff DH, Wojdyla K, Oxley D, Chessa T, Hudson K, Hawkins PT, Stephens LR, Barry ST, Okkenhaug K.
Frontiers in Immunology 12, 415
DOI: 10.3389/fimmu.2021.631271

 

C5a impairs phagosomal maturation in the neutrophil through phosphoproteomic remodelling

Wood, AJ, Vassallo, AM, Ruchaud-Sparagano, MH, Scott, J, Zinnato, C, Gonzalez-Tejedo, C, Kishore, K, D'Santos, CS, Simpson, AJ, Menon, DK, Summers, C, Chilvers, ER, Okkenhaug, K, Conway Morris, A. 
JCI Insight (2020).
DOI: 10.1172/jci.insight.137029.

 

Loss of Phosphatidylinositol 3-Kinase Activity in Regulatory T Cells Leads to Neuronal Inflammation

Stark AK, Davenport ECM, Patton DT, Scudamore CL, Vanhaesebroeck B, Veldhoen M, Garden OA, Okkenhaug K.
J Immunol. 2020. 205 (1) 78-89.
DOI: 10.4049/jimmunol.2000043

 

PI3Kδ hyper-activation promotes development of B cells that exacerbate Streptococcus pneumoniae infection in an antibody-independent manner

Stark AK, Chandra A, Chakraborty K, Alam R, Carbonaro V, Clark J, Sriskantharajah S, Bradley G, Richter AG, Banham-Hall E, Clatworthy MR, Nejentsev S, Hamblin JN, Hessel EM, Condliffe AM, Okkenhaug K.
Nat Commun. 2018. 9(1):3174. 
DOI: 10.1038/s41467-018-05674-8

 

Phosphoinositide 3-kinase δ inhibition promotes antitumor responses but antagonizes checkpoint inhibitors

Lim EL, Cugliandolo FM, Rosner DR, Gyori D, Roychoudhuri R, Okkenhaug K.
JCI Insight. 2018. 3(11). pii: 120626. 
DOI: 10.1172/jci.insight.120626

 

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

Pearce VQ, Bouabe H, MacQueen AR, Carbonaro V, Okkenhaug K.
J Immunol. 2015. 195(7):3206-17. 
DOI: 10.4049/jimmunol.1501227

 

Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer

Ali K, Soond DR, Pineiro R, Hagemann T, Pearce W, Lim EL, Bouabe H, Scudamore CL, Hancox T, Maecker H, Friedman L, Turner M, Okkenhaug K, Vanhaesebroeck B.
Nature. 2014. 510(7505):407-411.
DOI: 10.1038/nature13444

 

Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage

Angulo I, Vadas O, Garçon F, Banham-Hall E, Plagnol V, Leahy TR, Baxendale H, Coulter T, Curtis J, Wu C, Blake-Palmer K, Perisic O, Smyth D, Maes M, Fiddler C, Juss J, Cilliers D, Markelj G, Chandra A, Farmer G, Kielkowska A, Clark J, Kracker S, Debré M, Picard C, Pellier I, Jabado N, Morris JA, Barcenas-Morales G, Fischer A, Stephens L, Hawkins P, Barrett JC, Abinun M, Clatworthy M, Durandy A, Doffinger R, Chilvers ER, Cant AJ, Kumararatne D, Okkenhaug K, Williams RL, Condliffe A, Nejentsev S.
Science. 2013. 342(6160):866-71.
DOI: 10.1126/science.1243292

Other publications: 

 

Selected Review Articles:

PI3K inhibitors are finally coming of age

Vanhaesebroeck B, Perry MWD, Brown JR, André F, Okkenhaug K.
Nat Rev Drug Discov. 2021. 14. doi: 10.1038/s41573-021-00209-1.
Full text available here: https://rdcu.be/cmDLM

 

Phosphoinositide 3‐kinase δ is a regulatory T‐cell target in cancer immunotherapy

EL Lim, K Okkenhaug
Immunology. 2019. 157 (3), 210-218. 
DOI: 10.1111/imm.13082

 

PI3Kδ and primary immunodeficiencies 

Lucas CL, Chandra A, Nejentsev S, Condliffe AM, Okkenhaug K.
Nat Rev Immunol. 2016. 16(11):702-714.  Epub 2016 Sep 12. Review.
DOI 10.1038/nri.2016.93.

 

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

 

 
 
 

Teaching and Supervisions

Teaching: 

Professor Okkenhaug teaches the following courses:

Part 1B Biology of Disease (Immunology) 

Part II Pathology (Immunology)

Professor of Immunology
Head of the Division of Immunology
Professor Klaus  Okkenhaug

Contact Details

Department of Pathology
University of Cambridge
Tennis Court Road
CB2 1QP
Cambridge
CB2 1QP
Takes PhD students
Available for consultancy

Affiliations

Person keywords: 
Immunology
PI3K
Cancer
Infection