Pan-gynaecological Cancers Dr Takanori Kitamura Principal Investigator, Chancellor’s Fellow & MRC Career Development Fellow Contact details Email: tkitamur@exseed.ed.ac.uk Research summary Breast, ovarian, and endometrial cancers, sometimes grouped together as pan-gynaecological cancers, significantly affect women's reproductive health through their lifetimes. Our research aims to pioneer ground-breaking diagnostic tools and therapeutic approaches for pan-gynaecological cancers by investigating the characteristics and functions of non-malignant cells within tumours. Research interests We are particularly interested in the characteristics of various subpopulations of TAMs within pan-gynaecological cancers and their impacts on anti-tumour immune responses and therapeutic outcomes. Our current research interests are as follows: Exploring the distinctive phenotype of TAM subpopulations across different stages of tumours, as well as their involvements in the tumour progression. By this study, we aim to elucidate biomarkers to predict the progression and therapy response of pan-gynaecologic cancers. Investigating the molecular mechanisms through which TAMs exert suppressive effects on the anti-tumour functions of CD8+ T cells and NK cells. By dissecting these pathways, we seek to uncover novel targets for improvement of immunotherapies. Comparative analysis of the tumour microenvironment across breast, ovarian, and endometrial cancers, aiming to identify both shared and distinct features. By discerning similarities and differences in the composition and dynamics of the tumour microenvironment among these pan-gynaecological cancers, we aim to obtain insights that can inform tailored therapeutic strategies for each malignancy. Key projects Explore impacts of a TAM subset on the mammary tumour progression and anti-immune response Discover markers for spatially distinct TAM subsets within ductal carcinoma in situ (DCIS) Identify phenotype of circulating neutrophils in patients with breast or ovarian cancer Uncover characteristics of TLS-associated macrophages within breast & gynaecologic cancers Elucidate mechanisms behind TAM-mediated NK suppression in breast cancer Selected recent publications Kitamura T*. Tumour-associated macrophages as a potential target to improve natural killer cell-based immunotherapies. Essays Biochem (2023) EBC20230002. DOI: 10.1042/EBC20230002. (Review) Cheng Z, Thompson EJ, Mendive-Tapia L, Scott JI, Benson S, Kitamura T, Senan-Salinas A, Samarakoon Y, Roberts EW, Arias MA, Pardo J, Galvez EM, Vendrell M. Fluorogenic granzyme A substrates enable real-time imaging of adaptive immune cell activity. Angew Chem Int Ed Engl. (2022) e202216142. DOI: 10.1002/anie.202216142. Barth N, van Dalen F, Karmakar U, Bertolini M, Mendive-Tapia L, Kitamura T, Verdoes M, Vendrell M. Enzyme-activatable chemokine conjugates for in vivo targeting of tumor-associated macrophages. Angew Chem Int Ed Engl. (2022) 61: e202207508. DOI: 10.1002/anie.202207508. Scott JI, Mendive-Tapia L, Gordon D, Barth ND, Thompson EJ, Cheng Z, Taggart D, Kitamura T, Bravo-Blas A, Roberts EW, Juarez-Jimenez J, Michel J, Piet B, de Vries IJ, Verdoes M, Dawson J, Carragher NO, Connor RAO, Akram AR, Frame M, Serrels A, Vendrell M. A fluorogenic probe for granzyme B enables in-biopsy evaluation and screening of response to anticancer immunotherapies. Nat Commun. (2022) 13: 2366. DOI: 10.1038/s41467-022-29691-w. Scott J, Gutkin S, Green O, Thompson EJ, Kitamura T*, Shabat D*, Vendrell M*. A functional chemiluminescent probe for in vivo imaging of natural killer cell activity against tumours. Angew Chem Int Ed Engl. (2021) 60:5699-5703. DOI: 10.1002/anie.202011429. Brownlie D, Douthty-Shenton D, Soong DYH, Nixon C, Carragher NO, Carlin LM, Kitamura T*. Metastasis-associated macrophages constrain antitumor capability of natural killer cells in the metastatic site at least partially by membrane bound transforming growth factor β. J Immunother Cancer. (2021) 9: e001740. DOI: 10.1136/jitc-2020-001740 Kitamura T*, Kato Y, Brownlie D, Soong D, Sugano G, Kippen N, Li J, Doughty-Shenton D, Carragher N, Pollard JW. Mammary tumor cells with high metastatic potential are hypersensitive to macrophage-derived hepatocyte growth factor that promotes metastatic tumor growth in mice. Cancer Immunol Res. (2019) 7:2052-2064. DOI: 10.1158/2326-6066.CIR-19-0234. Kitamura T^*, Doughty-Shenton D^, Pollard JW, Carragher NO. Real time detection of in vitro tumor cell apoptosis induced by CD8+ T cells to study immune suppressive functions of tumor-infiltrating myeloid cells J. Vis. Exp. (2019) 143: e58841. DOI: 10.3791/58841. Cassetta L^, Kitamura T^*. Macrophage targeting: opening new possibilities for cancer immuno-therapy. Immunology. (2018) 155: 285-293. DOI: 10.1111/imm.12976 (Review) Kitamura T*, Doughty-Shenton D, Cassetta L, Fragkogianni S, Brownlie D, Kato Y, Carragher N, Pollard JW. Monocytes differentiate to immune suppressive precursors of metastasis-associated macrophages in mouse models of metastatic breast cancer. Front Immunol. (2018) 8: 2004. DOI: 10.3389/fimmu.2017.02004. Group members Florent Petitprez - PostDoc Jess Webb - Technician Nicola Graham - PostDoc Nikolaos Giannakis - PostDoc Sheila Webb - PostDoc Collaborators Professor Neil Carragher (CRUK Scotland Centre and Edinburgh Cancer Research) Professor Marc Vendrell (Centre for Inflammation Research) Professor Mike Dixon (Edinburgh Breast Unit, Western General Hospital) Dr Arran Turnbull (Edinburgh Cancer Research Centre) Professor Lisa Coussens (Oregon Health & Science University) Dr Maciej Parys (Roslin Institute, University of Edinburgh) Funders UK Research and Innovation (UKRI), Cancer Research UK (CRUK), Scottish Universities Life Sciences Alliance (SULSA), Wellcome Trust (WT-iTPA) HTML This article was published on 2024-09-10
