The role of the tetraspanin6 (TSPAN6) in regulating the immune microenvironment in inflammatory breast cancer (IBC)

Zhang, Jing (2023). The role of the tetraspanin6 (TSPAN6) in regulating the immune microenvironment in inflammatory breast cancer (IBC). University of Birmingham. Ph.D.

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Abstract

Inflammatory breast cancer (IBC) is a rare and aggressive type of invasive breast cancer with poor outcomes. Previous studies demonstrated that IBC is characterised by an abundance of tumour-infiltrating immune cells. However, the mechanism(s) underlying the IBC-controlling accumulation of various immune cells remained unclear. By performing standard trans-well experiments under two time intervals (4-hour and 16-hour), we demonstrated that the medium conditioned by IBC cells (CM-IBC) was chemotactic for B lymphocytes. More importantly, we discovered that Tspan6, a poorly-studied tetraspanin, strengthened the chemoattractive potential of IBC for B cells. Through “immune cell depletion and supplementation” experiments, we uncovered the cellular pathways (i.e. monocyte-dependent, monocyte/CD8+ T lymphocyte-dependent and Pertussis Toxin (PTX)-sensitive pathways) by which Tspan6-expressing IBC cells enhanced the migration of B cells. With regard to the molecular pathway, we identified that syntenin-1, the only known partner protein of Tspan6, played a vital role in regulating the Tspan6-dependent migration of B cells. The disassociation of Tspan6 and syntenin-1 significantly attenuated the chemoattractive potential of IBC cells for B lymphocytes. In addition, the downstream effector, Src kinase and p38 MAPK, appeared to involve in the Tspan6-syntenin-1-dependent migration of B cells. In conclusion, we uncovered intracellular and extracellular pathways by which Tspan6-expressing IBC cells could enhance the migration of B cells. These findings may provide more insights into the complicated immune networks in IBC and provide novel targets for anti-tumour therapeutics.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):