Research interests
In recognition of the rising successes in treatment of previously incurable cancers by harnessing the immune system, research in ‘cancer immunotherapy’ has been gaining immense momentum in recent years. In this regard tumours are commonly infiltrated by leukocyte subsets which may help drive their growth and survival. Either removing or reprogramming these suppressive tumour-associated leukocytes offers a viable strategy for promoting the effectiveness of various immunotherapeutic approaches to cancer, including monoclonal antibodies (mAb) and vaccines. Dr Roghanian’s group primarily focuses on cancer immunotherapy and the role of immune inhibitory receptors expressed on immune and/or tumour cells, and their influence on the tumour microenvironment. He takes advantage of novel engineered humanized mouse models of cancers to address such questions.
Inhibitory leukocyte immunoglobulin-like receptors (LILRB) / CD85 receptor family
The immune-regulating LILR family of receptors presents a potential point of intervention as they are expressed on leukocytes and are commonly dysregulated in tumours. In particular, the inhibitory LILRBs are attractive targets as they are highly expressed and relatively restricted to cells of the myeloid lineage.
We have previously demonstrated that LILRB1 ligation during human dendritic cell (DC) differentiation results in a population of immature DCs with poor T cell stimulating capacity (Young et al., Blood, 2008; Khanolkar et al., JLB, 2016) and revealed that LILRB1 ligation significantly altered the expression of a large number of genes with immune and cytoskeletal functions (Roghanian and Young, unpublished data). Likewise, human LILRB1 Tg mice have been shown to have a higher percentage of myeloid-derived suppressor cells with enhanced suppressive activity in vivo. In collaboration with BioInvent (Sweden) we have since produced a unique panel of specific fully human mAbs against LILRBs. Our novel observations indicate that these mAbs confer agonistic/antagonistic activities and are potent immunomodulators in vitro/vivo. Current research in the group aims to explore the therapeutic potential of LILRB1-3 antibodies in a number of different settings, including CAR T cell therapy. This is performed by assessing leukocytes isolated from healthy individuals and cancer patients; and by employing novel pre-clinical humanized mouse platforms reflecting human lymphomas and leukaemia with the matched immune system.
Anti-tumour activity of inhibitory Fc gamma receptor IIB (FcγRIIB / CD32B) antibodies in vivo
Therapeutic antibodies have transformed cancer therapy, unlocking new mechanisms of action by engaging the immune system. Unfortunately, cures rarely occur and patients display intrinsic or acquired resistance. Recently, Prof Cragg’s group demonstrated the therapeutic potential of targeting human FcγRIIB, a receptor implicated in immune cell desensitisation and tumour cell resistance, and have shown that FcγRIIB-blocking antibodies prevent internalization of certain therapeutic mAbs (e.g., rituximab), thereby maximizing cell surface accessibility and immune effector cell mediated anti-tumour activity (Lim et al., Blood 2011; Vaughan et al., 2013). Ongoing work within the Antibody and Vaccine Group, in collaboration with BioInvent, is using unique mAbs specific for human and mouse FcγRIIB, respectively, and a variety of FcγRIIB conditional knockout and transgenic (Tg) mouse models to dissect the mechanism of FcγRIIB in regulating mAb therapy in vivo (Roghanian et al., Cancer Cell, 2015 and unpublished data). We aim to unravel the FcγRIIB signalling in target (B cells) and effector cells (macrophages) and the subsequent net effect on mAb therapy.
Targeting the inhibitory FcγRIIB to augment immune responses in vivo
Inhibitory receptors, such as FcγRIIB, play an important role in maintaining the activation threshold of the immune system by permitting beneficial immune responses to develop, whilst preventing deleterious autoimmune reactions. FcγRIIB is expressed on monocytes and professional antigen-presenting cells, and is the predominant FcγR present on B cells. We are taking advantage of specific mouse and human FcγRIIB mAbs as well as FcγRIIB Tg/KO mice and pre-clinical models (Williams et al., Eur J Immunol, 2012; Roghanian et al., Cancer Cell, 2015) to explore the potential of FcγRIIB as a target for manipulating the immune responses against foreign antigens and tumour cells.
Overcoming bone marrow (BM) resistance
Lymphoma and leukaemia frequently display involvement of the BM. Although chemoimmunotherapies effectively clear neoplastic cells from the circulation and most lymphoid tissues, a notable portion of malignant cells often persist in the BM, indicating that it provides a treatment-resistant microenvironment, increasing recurrence. We and others believe that in addition to delivering protection from chemo-induced apoptosis, the BM niche also impairs the effector mechanisms of mAb; most likely by suppressing the myeloid effector cells (EF), such as lowering their activatory to inhibitory Fcγ receptor (FcγR) ratios. To unravel such immunosuppressive mechanisms, we are studying functional and transcriptional differences in human and mouse EFs from different anatomical compartments conducive or resistant to mAb depletion, i.e., spleen versus BM, from humanized mice and patients. Furthermore, we are investigating the cross-talk between BM mesenchymal stromal cells (MSC) and EFs, with a focus on identifying the pathways regulating their cytotoxic/phagocytic potential. Lastly, we are examining the potential of therapeutic regulators of BM EFs, such as cyclophosphamide (CTX; Pallasch et al., Cell, 2014) and FcγRIIB/CD32B blocking mAbs (Roghanian et al., Cancer Cell, 2015), to enhance immunotherapy. These detailed studies will provide important new insights into the immunosuppressive BM niche, facilitating targeting of such pathways for enhanced mAb-therapy in niche-specific resistant organs.
Strong candidates with own funding interested in joining the group (graduate studentships, post-doctoral positions [non-clinical and clinical] and overseas fellows) are encouraged to contact Dr Roghanian directly (A.Roghanian@soton.ac.uk) with a recent CV and statement.
Research group
Cancer Sciences
Dr Ali RoghanianAntibody & Vaccine Group
Centre for Cancer Immunology
University Hospital Southampton (MP127)
Tremona Road, Southampton SO16 6YD
Email: A.Roghanian@soton.ac.uk
Room Number : SGH/CCI 3007/MP127
Facsimile: (023) 8070 4061
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