Fundamental immunosuppressive pathway determining ability of cancer and embryonic cells to escape cytotoxic immune attack

Nowadays rapid gaining of knowledge on cancer progression and mutagenesis has enabled the development of improved diagnostics and therapeutic approaches to be used in medicine. Yet, cancer is still one of the most dangerous diseases, especially in Europe, Asia, and America. This is due to rapid mutation of cancer cells and high costs of most therapies. A change in application of treatments is necessary to improve the survival of cancer patients, especially the development of personalized cancer therapy and establishment of easily accessible targets are needed.

In the last 20 years the proteins Tim-3, galectin-9 and VISTA have been investigated regarding their influence on cancer development. While a significance was determined in their ability of suppressing immune responses, the exact mechanisms have not been researched yet. Structural analysis has deemed these proteins as being able to interact with each other and results so far indicate that by formation of protein complexes these proteins are able to efficiently inhibit cytotoxic immune responses.

To investigate the immunosuppressive effects induced by interactions between these proteins and the ability to form such multi-protein complexes as receptors and ligands we used quantitative and qualitative experimental approaches. We analyzed a variety of cancer cell lines and primary cancer samples as well as embryonic cell lines and primary fetal samples.

We were able to not only verify for the first time that galectin-9 is a ligand of VISTA, but we were also able to determine that the same mechanisms used by embryonic cells to adapt to the mother's immune system can be reused later in life by cancer cells to inhibit cytotoxic immune responses. Furthermore, we were able to prove that each of these proteins is supported by the TGF-β - Smad-3 pathway, which is also able to self-sustain the production of TGF-β in an autocrine/paracrine fashion. Data gained during the investigation of galectin-9 expression levels within other organisms also indicate that this protein is evolutionary conserved.

Our results clearly show that understanding the exact mechanisms of this pathway will allow us to develop targeted, personalized and easily applicable immunotherapy in the future by determining the key factors in individual tumour types focusing on the Tim-3 - galectin-9 - VISTA pathway.