Arming T cells with chemokine receptors for cancer therapy
Engineered T cells have changed the treatment landscape in several hematological malignancies. In contrast, beyond anecdotal reports, no efficacy could be demonstrated to this day in solid tumors. A critical difference to the aforementioned leukemia and other lymphoma is the access of therapeutic cells to cancer cells in tumor tissue. Such environment is typically badly vascularized, hypoxic and tends to exclude inflammatory immune cells. In principle, the entry of immune cells to such tissue is a tightly regulated process involving integrins, chemoattractants (chemokines) and their matching receptors. This process does not seem to be deficient per se in most cancer, as they tend to attract different types of immune suppressive population via said mechanism. A major problem rather seem to be the more selective use of attracting pathways not typically expressed on therapeutic or other pro-inflammatory cells. At the same time, this mismatch also presents a window of opportunity for therapeutic exploitation.
In my talk, I will demonstrate how cancer tissue excludes therapeutic T cells by ligand selection and how this capacity can be restored by introducing adequate chemokine receptors into therapeutic T cells. I will show that both pro- and anti-inflammatory chemokine-chemokine receptor axis can be used for the task. Focussing on pancreatic cancer, I will showcase examples how such strategy can boost chimeric antigen receptor (CAR) T cell activity in a range of syngeneic, xenograft and patient-derived models in vitro and in vivo and point towards an avenue for clinical translation.