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Dissecting how breast cancer-associated inflammation shapes invariant natural killer T cell activity during metastatic progression

Project description

Comprehensive study of specific T cell activity during breast cancer metastatic progression

Breast cancer is the second most common cancer in women. Improvement of the response of metastatic breast cancer to immunotherapeutic checkpoint blockade requires a better understanding of the particular immune landscape. Invariant natural killer T (iNKT) cells are specialised T cells that recognise lipid antigens. iNKT antitumour potential has been underinvestigated as they are scarcely present in cancer patients. The EU-funded BreaKer project works with the hypothesis that iNKT cells’ scarce presence and poor activation is a result of cancer-induced immunosuppressive mechanisms. The project objective is to carry out a comprehensive study of iNKT cell immunophenotype and activation mechanisms in metastatic breast cancer patients as well as healthy individuals to develop novel combinatorial immunotherapies for metastatic breast cancer.

Objective

Breast cancer is the second cause of cancer-related death in women. Although cancer immunotherapy emerged as a successful therapy for many cancer types, the response of metastatic breast cancer patients to immune checkpoint blockade remains disappointing, urging for a better understanding of the breast cancer immune landscape. iNKT cells are lipid-specific T cells that bridge innate and adaptive immunity and exert a plethora of immune functions depending on tissue distribution. Despite their known antitumor potential, they have been largely overlooked in the cancer field for their content paucity in cancer patients. I hypothesize that their scarce abundance and poor activation status is caused by cancer-induced immunosuppressive mechanisms. Indeed, I observed that circulating and metastasis-infiltrating iNKT cells are functionally impaired in the K14cre;Cdh1F/F;Trp53F/F(KEP)-based mouse model of de novo breast cancer metastases. With a translational approach, I will provide an unprecedented comprehensive dataset comparing iNKT cell immunophenotype in metastatic breast cancer patients and healthy controls. Next, I will generate human iNKT cell lines to perform in vitro mechanistic studies aimed at assessing how cancer-associated inflammation can modulate iNKT cell antitumor activity. Moreover, the innovative use of iNKT cell deficient Jα18-/- mice coupled to the KEP-based model of breast cancer metastases, will offer a clear picture of the role of iNKT cells and their cancer-associated cellular networks during the metastatic cascade. Finally, I will in vivo deplete immunosuppressive cells to unleash iNKT cell antitumor activity. My solid knowledge of iNKT cell biology combined with the expertise in breast cancer-associated inflammation of the hosting lab and the cutting-edge clinical research of the institute will uniquely generate fundamental knowledge with high applicative potential for the design of novel combinatorial immunotherapies for metastatic breast cancer.

Coordinator

STICHTING HET NEDERLANDS KANKER INSTITUUT-ANTONI VAN LEEUWENHOEK ZIEKENHUIS
Net EU contribution
€ 175 572,48
Address
PLESMANLAAN 121
1066 CX Amsterdam
Netherlands

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Region
West-Nederland Noord-Holland Groot-Amsterdam
Activity type
Research Organisations
Links
Total cost
€ 175 572,48