Role of RORyt+ Innate Lymphoid Tissue Inducer Cells within breast cancer microenvironments

Abstract

Within invasive breast cancers, lymphatic invasion is thought to be the first step tumour cells undertake when metastasizing through the lymphatic vasculature. The presence of lymphatic metastasis has been shown to stratify breast cancer phenotypes into distinct prognostic groups. The exact molecular mechanisms mediating tumour cell entry and dissemination within the lymphatic system remain unclear. We report the first identification of RORyt+-innate lymphoid
tissue inducer (LTi) cells within the human breast cancer tumour microenvironment and the enrichment of lymphoid chemokines/chemokine receptor gene signature within an aggressive breast cancer subtype. The presence of these cells within the tumour microenvironment was shown to correlate with both an increased lymphatic vessel density (LVD) and tumour invasion into
lymphatic vessels. We demonstrate the CCL21-dependent recruitment of LTi cells into breast tumours, the CXCL13-dependent interaction between the tumoural LTi and stromal cells and the downstream effect of the CXCL13 positive feedback loop in promoting lymphatic tumour cell motility via the RANK-RANKL axis. These data suggest a novel role for LTi cells in enhancing lymphatic invasion of tumour cells through modulation of the local lymphoid chemokine profile.

Date of Award	2014
Original language	English
Awarding Institution	King's College London
Supervisor	Tony Ng (Supervisor) & Andrew Tutt (Supervisor)