Tspan6 as a regulator of immune microenvironment in breast cancer

Growth of tumour is controlled at the multiple levels which involved changes in tumour cell responses to extracellular signals. Conversely, tumour cells themselves modify surrounding tissue by reorganising its architecture and cellular composition. It is very important to understand how tumour cells cross communicate with microenvironment as this will help to design novel therapeutic approaches.

The proposed work is focussed on breast cancer and specifically centred on examining new pathways of communications between tumour cells and B-cells which contribute to anti-tumour host defence. We have discovered that the abundance of a cell surface molecule called Tspan6 is decreased during cancerous progression. Importantly, loss or decrease in the level of Tspan6 correlated with worse patient survival. We have also noticed that when Tspan6 was abundant on breast tumour cells the cancerous tissues were enriched in a specific type of lymphocytes. This observation led us to hypothesise that when expressed in breast cancer cells Tspan6 might control the process anti-tumour host responses. The outlined programme will investigate molecular processes that would explain this phenomenon. Specifically, we will use breast cancer tissues to examine whether Tspan6 exhibits specific preferences towards various subtypes of lymphocytes in directing their ability to accumulate in cancerous tissues. We will identify Tspan6-dependent molecular factors derived from tumour cells that control accumulation of lymphocytes in cancerous tissues. We will also examine how Tspan6 change an intracellular network of signalling processes that underly the ability of tumour cells to influence recruitment and/or retention of B-cells in cancerous tissues.

The immune cell landscape within tumour microenvironment is controlled by an elaborate network of communications involving chemokines, cytokines and growth factors which are produced by the immune cells themselves, by cancer cells and by other cell types in cancerous tissues (e.g. tumour endothelium, tumour-associated fibroblasts). Whilst specific contribution of various types of tumour-infiltrating T-cells and macrophages to tumour development and host-immune responses is becoming clearer, significantly less is known and understood about the function of tumour-infiltrating B-cells (TIL-B).

Whilst studying the immune landscape in breast cancer we discovered that the abundance of TIL-B correlated with the expression of tetraspanin 6 (Tspan6) by tumour cells. Importantly, Tspan6-expressing breast cancer cells stimulated migration of B-lymphocytes in vitro. These observations point towards a novel pathway underlying communication between tumour cells and TIL-B. As the expression of Tspan6 positively correlated with patients survival, we hypothesise that that Tspan6 suppresses breast cancer progression by modulating tumour infiltration of B-cells and, consequently, the immune landscape of tumour tissues. The proposed work aims to investigate the molecular pathways underlying the phenomenon of increased B-cell chemotaxis towards Tspan6-expressing breast cancer cells.
We will:
-establish the contribution of chemotactic factors differentially produced by Tspan6-expressing breast cancer cells.
-delineate Tspan6-dependent pathways in breast cancer cells that control infiltration of B-cells to cancerous tissues.
-examine the B-cell profile in breast cancer tissues in relation to expression of Tspan6.
-evaluate the role of Tspan6-dependent recruitment of B-cells to cancerous tissues in vivo.

The applicants are already actively involved in outreach activities which are organised by the School of Cancer Sciences in Birmingham. This involves lectures to the general public and lab tours. All have excellent contacts with clinical colleagues at the University Hospital Birmingham and Heartlands Hospital. The principal applicant has recently organised an International Symposium on the Inflammatory breast cancer which involved patient advocates and was covered in a press release by the Breast Cancer Now.

All these activities will continue during the life-time of the grant.

Commercial engagement:
Pharmaceutical and biotech companies are learning about the technologies being developed here through partnerships and visits to Birmingham. The applicants will take further steps to engage with pharma and biotech companies.