Life Sciences Research for Lifelong Health

Klaus Okkenhaug

Klaus Okkenhaug is now Professor of Immunology at the University of Cambridge. Visit his page there for full details of his current research.

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.

Latest Publications

Compensation between CSF1R+ macrophages and Foxp3+ Treg cells drives resistance to tumor immunotherapy.
Gyori D, Lim EL, Grant FM, Spensberger D, Roychoudhuri R, Shuttleworth SJ, Okkenhaug K, Stephens LR, Hawkins PT

Redundancy and compensation provide robustness to biological systems but may contribute to therapy resistance. Both tumor-associated macrophages (TAMs) and Foxp3+ regulatory T (Treg) cells promote tumor progression by limiting antitumor immunity. Here we show that genetic ablation of CSF1 in colorectal cancer cells reduces the influx of immunosuppressive CSF1R+ TAMs within tumors. This reduction in CSF1-dependent TAMs resulted in increased CD8+ T cell attack on tumors, but its effect on tumor growth was limited by a compensatory increase in Foxp3+ Treg cells. Similarly, disruption of Treg cell activity through their experimental ablation produced moderate effects on tumor growth and was associated with elevated numbers of CSF1R+ TAMs. Importantly, codepletion of CSF1R+ TAMs and Foxp3+ Treg cells resulted in an increased influx of CD8+ T cells, augmentation of their function, and a synergistic reduction in tumor growth. Further, inhibition of Treg cell activity either through systemic pharmacological blockade of PI3Kδ, or its genetic inactivation within Foxp3+ Treg cells, sensitized previously unresponsive solid tumors to CSF1R+ TAM depletion and enhanced the effect of CSF1R blockade. These findings identify CSF1R+ TAMs and PI3Kδ-driven Foxp3+ Treg cells as the dominant compensatory cellular components of the immunosuppressive tumor microenvironment, with implications for the design of combinatorial immunotherapies.

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JCI insight, 3, 2379-3708, , 2018

PMID: 29875321

Phosphoinositide 3-kinase δ inhibition promotes antitumor responses but antagonizes checkpoint inhibitors.
Lim EL, Cugliandolo FM, Rosner DR, Gyori D, Roychoudhuri R, Okkenhaug K

Multiple modes of immunosuppression restrain immune function within tumors. We previously reported that phosphoinositide 3-kinase δ (PI3Kδ) inactivation in mice confers resistance to a range of tumor models by disrupting immunosuppression mediated by regulatory T cells (Tregs). The PI3Kδ inhibitor idelalisib has proven highly effective in the clinical treatment of chronic lymphocytic leukemia and the potential to extend the use of PI3Kδ inhibitors to nonhematological cancers is being evaluated. In this work, we demonstrate that the antitumor effect of PI3Kδ inactivation is primarily mediated through the disruption of Treg function, and correlates with tumor dependence on Treg immunosuppression. Compared with Treg-specific PI3Kδ deletion, systemic PI3Kδ inactivation is less effective at conferring resistance to tumors. We show that PI3Kδ deficiency impairs the maturation and reduces the capacity of CD8+ cytotoxic T lymphocytes (CTLs) to kill tumor cells in vitro, and to respond to tumor antigen-specific immunization in vivo. PI3Kδ inactivation antagonized the antitumor effects of tumor vaccines and checkpoint blockade therapies intended to boost the CD8+ T cell response. These findings provide insights into mechanisms by which PI3Kδ inhibition promotes antitumor immunity and demonstrate that the mechanism is distinct from that mediated by immune checkpoint blockade.

+ View Abstract

JCI insight, 3, 2379-3708, , 2018

PMID: 29875319

Non-Invasive Multiphoton Imaging of Islets Transplanted Into the Pinna of the NOD Mouse Ear Reveals the Immediate Effect of Anti-CD3 Treatment in Autoimmune Diabetes.
Benson RA, Garcon F, Recino A, Ferdinand JR, Clatworthy MR, Waldmann H, Brewer JM, Okkenhaug K, Cooke A, Garside P, Wållberg M

We present a novel and readily accessible method facilitating cellular time-resolved imaging of transplanted pancreatic islets. Grafting of islets to the mouse ear pinna allows non-invasive, longitudinal imaging of events in the islets and enables improved acquisition of experimental data and use of fewer experimental animals than is possible using invasive techniques, as the same mouse can be assessed for the presence of islet infiltrating cells before and after immune intervention. We have applied this method to investigating therapeutic protection of beta cells through the well-established use of anti-CD3 injection, and have acquired unprecedented data on the nature and rapidity of the effect on the islet infiltrating T cells. We demonstrate that infusion of anti-CD3 antibody leads to immediate effects on islet infiltrating T cells in islet grafts in the pinna of the ear, and causes them to increase their speed and displacement within 20 min of infusion. This technique overcomes several technical challenges associated with intravital imaging of pancreatic immune responses and facilitates routine study of beta islet cell development, differentiation, and function in health and disease.

+ View Abstract

Frontiers in immunology, 9, 1664-3224, 1006, 2018

PMID: 29867981

Group Members

Latest Publications

Regulatory T Cell Migration Is Dependent on Glucokinase-Mediated Glycolysis.

Kishore M, Cheung KCP, Fu H

Immunity
47 1097-4180:875-889.e10 (2017)

PMID: 29166588

Multi-tissue DNA methylation age predictor in mouse.

Stubbs TM, Bonder MJ, Stark AK

Genome biology
18 1474-760X:68 (2017)

PMID: 28399939

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