Probing CD28 as checkpoint for T cell co-stimulation in cancer and infection

Regulation of T cells has been a cornerstone in the development of therapeutics for fighting a wide plethora of pathologies, including cancer, chronic infections and disease.

The mechanisms governing activation or repression of T cells depend on several receptors which provide second signals following the initial interaction with APCs presenting MHC complexes. Among these receptors, CD28 constitutes the main interest for this project. Its role as co-stimulator of T cell activity is known for so long.

However, the particular mechanisms underlying its effective interaction with its cognate ligands (CD80/CD86) remain unclear yet.

In particular, the present project is aimed at exploring the possible role of sialic acid in regulation of CD28 co-stimulatory activity (via inhibition), which could provide a novel explanation for the so-called neuraminidase effect described for decades.

This effect leads to enhanced antigen-mediated T cell activation when sialic acids are enzymatically removed, but its origin is uncertain.

Additionally, the structural basis for CD28 regulation will be explored, putting an special emphasis on its exploitation for the design of molecular platforms which may serve for reactivation of exhausted T cells in tumor models.

The proposed project will be jointly undertaken by two renowned groups with large and solid experience in the field of glycomics, at CIC bioGUNE (J. Jimnez-Barbero) and Scripps (J.C. Paulson).

The applicant, under their guidance, will develop the project from a very wide and cross-disciplinar perspective, covering all unknown aspects related to CD28 so far as well as proposing a novel methodology to translate this knowledge into valuable goods for society.

The success of the project will likewise have a remarkable impact in the field of immunotherapy-based treatments for patients with cancer or chronic infections.