Targeting the Tumour Microenvironment

Significant advances in research have involved targeting, not only malignant cells directly, but also the non-malignant tumour microenvironment (TME). Targeting the interactions between malignant cells and the TME is critical for cancer treatments.

Theme Leads: Professor Kairbaan Hodivala-Dilke, Professor Fran Balkwill

Key Cancer Types: pancreatic, lung, bladder, haematological, ovarian, breast

Research Focus Key Achievements Key Publications

Research Focus

The main areas of focus are as follows:

Defining how different tumours direct unique microenvironments
Characterising and overcoming immune suppression in the tumour microenvironment
Stratifying tumour microenvironment treatment approaches
Targeting cancer-associated fibroblasts, tumour associated macrophages and the malignant extracellular matrix
Exploitation of tumour endothelial cells for improved cancer treatment
Building tumour microenvironment models of the future
Understanding if more invasive and metastatic cells have greater impact on the tumour microenvironment

Key Achievements

Established that aberrant PD-L1 expression by lymphoma cells and increased expression of PD-1 on T cells are key mediators of impaired anti-tumour immune responses in a range of B-cell lymphomas
Developed strategies to enhance the efficacy of chemotherapy and immunotherapy in lung cancer by modulating the vasculature
Generated a template and validation for human 3D multi-cellular models
Developed an intravenously deliverable tumour-targeted oncolytic vaccinia virus armed with immune modulatory molecule. Intravenous injection of this virus combined with anti-PD-1 antibody can eradicate the established pancreatic tumour

Key Publications

Clinical activity and molecular correlates of response to atezolizumab alone and in combination with bevacizumab. McDermott DF et al. (27 authors), Powles T (last author). Nat Med (2018) 24(6):749-757. PMID: 29867230

Expression of FOXP3, CD68, and CD20 at diagnosis in the microenvironment of classical Hodgkin lymphoma is predictive of outcome. Greaves P, Clear A, Coutinho R, Wilson A, Matthews J, Owen A, Shanyinde M, Lister TA, Calaminici M, Gribben JG. J Clin Oncol (2013) 31(2):256-262. PMID: 23045593

Follicular lymphoma cells induce changes in T-cell gene expression and function: potential impact on survival and risk of transformation. Kiaii S, Clear AJ, Ramsay AG, Davies D, Sangaralingam A, Lee A, Calaminici M, Neuberg DS, Gribben JG. J Clinl Oncol (2013) 31(21):2654-2661. PMID: 23775959

Deconstruction of a Metastatic Tumor Microenvironment Reveals a Common Matrix Response in Human Cancers. Pearce OMT, et al (11 authors), Gribben JG, Jones JL, Kocher HM, Lockley M, (9 authors), BalkwillFR (last author). Cancer Discovery (2018) 8(3):304-319. PMID: 29196464

A vaccinia virus armed with interleukin-10 is a promising therapeutic agent for treatment of murine pancreatic cancer. Chard LS et al (17 authors), Lemoine NR, Wang Y (last author). Clin Cancer Res (2015) 21(2):405-416. PMID: 25416195

Activated pancreatic stellate cells sequester CD8+ T cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma. Ene-Obong A, Clear AJ, Watt J, Wang J, Fatah R, Riches JC, Marshall JF, Chin-Aleaong J, Chelala C, Gribben JG, Ramsay AG, Kocher HM. Gastroenterology (2013) 145(5):1121-1132. PMID: 23891972

Dual-action combination therapy enhances angiogenesis while reducing tumor growth and spread. Wong PP et al (13 authors), Kocher HM, Hodivala-Dilke KM (last author). Cancer Cell (2015) 27(1):123-137. PMID: 25584895

Endothelial-cell FAK targeting sensitizes tumours to DNA-damaging therapy. Tavora B et al (16 authors), Gribben JG, Hodivala-Dilke KM (last author). Nature (2014) 514(7520):112-116. PMID: 25079333

Reactivation of p53 by a Cytoskeletal Sensor to Control the Balance Between DNA Damage and Tumor Dissemination. Herraiz C et al (8 authors) and Sanz-Moreno V (last author). J Natl Cancer Inst (2015) 108(1). PMID: 26464464

Diverse matrix metalloproteinase functions regulate cancer amoeboid migration. Orgaz JL et al (11 authors) and Sanz-Moreno V. Nat Commun (2014) 5:4255. PMID: 24963846