Centre for Reproductive Health
Centre for Reproductive Health
Institute for Regeneration and Repair
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Dr Takanori Kitamura

Background and research interest.

Dr Takanori Kitamura

Principal Investigator, Chancellor’s Fellow & MRC Career Development Fellow

Contact details

Address

Street

The Centre for Reproductive Health
Institute for Regeneration and Repair (IRR)
4-5 Little France Drive
Edinburgh BioQuarter

City
Edinburgh
Post Code
EH16 4UU

Background

Takanori Kitamura obtained his Ph.D. in 2003 in Biochemistry from Graduate School of Veterinary Medicine, Hokkaido University (Japan). He then joined Graduate School of Medicine, Kyoto University (Japan) as a research fellow/assistant professor where he worked on the roles of myeloid cells in intestinal cancer progression using GEM models (Nat Genet 2007, PNAS 2010). In 2010, he joined Professor Jeffrey Pollard’s group at Albert Einstein College of Medicine (U.S.A.) as a research associate, and studied the role of tumour-associated macrophages in breast cancer metastasis (Nat Rev Immunol 2015, J Exp Med 2015). In 2013, he was recruited to the MRC Centre for Reproductive Health at the University of Edinburgh as a Chancellor’s Fellow to establish his independent research group.

Tumour metastasis has been a leading cause of cancer death, indicating that current immunotherapy and chemotherapy have had limited success in treating the disease. It is thus necessary to find novel approaches to suppress the expansion of metastatic tumors to prolong patient’s survival.

Data from mouse models including ours suggest that tumour-infiltrating myeloid cells, such as tumour-associated macrophages (TAMs) and neutrophils (TANs) promote metastatic processes in several tumor types such as breast, colon, and lung cancer. TAMs and TANs are also reported to protect cancer cells from immune rejection by CD8+ T and NK cells and to restrict efficacy of cytotoxic drugs at the primary sites.

These data suggest that keeping out and/or suppressing these pro-metastatic stromal cells is an attractive strategy to restrict metastatic tumour growth by withdrawal of environmental supports and by increasing efficiency of current therapeutic modalities for metastatic diseases. We are thus interested in the cooperative actions of these cells for metastatic tumor growth and effects on cytotoxic cells and drugs at the secondary sites.

Research Interest

Breast cancer is the leading cause of cancer related death in women mainly by the formation of metastatic tumors that are incurable by current therapies. After the success of checkpoint inhibitors, immunotherapies aimed at boosting anti-tumour functions of CD8+ T cells have been re-evaluated as an effective therapy. However, its efficacy is limited in certain types of malignant tumors including metastatic breast cancer. Recent studies indicate that not only adaptive immune cells (e.g., CD8+ T cells) but also innate immune cells (e.g., NK cells) are important component of anti-tumor immune reactions, and thus NK cells are highlighted as a novel and promising therapeutic tool. On the other hand, studies suggest that other types of innate immune cells (e.g., neutrophils and macrophages) may restrict anti-tumour functions of these cytotoxic lymphocytes and thus limit efficacy of immunotherapies.

Using in vivo and in vitro models of metastatic breast cancer, we identified that TAMs in the metastatic site can directly suppress cytotoxicity of CD8+ T cells and NK cells. These data suggest that TAMs play pivotal roles in the establishment of immune suppressive environment in metastatic breast cancer. Our overall objectives are to understand innate immunity in the metastatic tumor microenvironment and thereby develop new immunotherapeutic approaches. The current research topics of our group are as follows;

  •  To identify mechanisms by which TAMs suppress NK cell cytotoxicity against breast cancer cells
  •  To find small molecule compounds that can block TAM-mediated NK cell suppression
  •  To investigate correlation between TAM accumulation and recruitment/activation of cytotoxic lymphocytes in canine solid tumours

 

Staff/group members

  • Dr Dahlia Doughty Shenton, Postdoctoral Fellow

 

Grants 

  •  MRC Career Development Award, £1,103,522 (2019-2024)
  •  DogsTrust Canine Welfare Grant, £90,935 (2020-2022)

 

Publications

(^ Equal contribution, * Correspondence)

1. 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. 

2. Fernandez A, Thompson EJ, Pollard JW, Kitamura T*, Vendrell M*. A fluorescent activatable AND-gate chemokine CCL2 enables in vivo detection of metastasis-associated macrophages. Angew Chem Int Ed Engl. (2019) 58: 1-6. DOI: 10.1002/anie.201910955

3. 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

4. Argyle D, Kitamura T*. Targeting macrophage-recruiting chemokines as a novel therapeutic strategy to prevent the progression of solid tumors. Front Immunol. (2018) 9: 2629. DOI: 10.3389/fimmu.2018.02629

5. Cassetta L^, Kitamura T^*. Macrophage targeting: opening new possibilities for cancer immuno-therapy. Immunology. (2018) 155: 285-293. DOI: 10.1111/imm.12976

6. Cassetta L^, Kitamura T^*. Targeting tumor-associated macrophages as a potential strategy to enhance the response to immune checkpoint inhibitors. Front Cell Dev Biol. (2018) 6: 38. DOI: 10.3389/fcell.2018.00038

7. 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. 

8. Kitamura T, Pollard JW, Vendrell M. Optical windows for imaging the metastatic tumour microenvironment in vivo. Trends Biotechnol. (2017) 35: 5-8. DOI: 10.1016/j.tibtech.2016.05.001

9. Rodriguez C, Kitamura T, Kato Y, Pollard J, Condeelis J, Entenberg D. Long-term high-resolution intravital microscopy in the lung with a vacuum stabilized imaging window. J Visual Exp (2016) 116. DOI: 10.3791/54603.

 

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