Within this project we have identified a number of critical parameters that influence the sensitivity of human tumors to T cell attack. In one major research line we have determined that a large fraction of the T cells that reside in certain human tumors is not tumor-reactive and can hence be considered bystanders, and that these cells may be distinguished from tumor reactive T cells based on both phenotypic and functional properties. This observation is likely to explain - at least in part - the low response rate to immune checkpoint blocking antibodies that is observed in these cancers. In addition, this observation provides a very strong incentive for the development of both vaccination and adoptive T cell transfer-based approaches that can be used to increase the magnitude of the tumor reactive T cell response. Finally, this work provides a potential avenue to develop improved predictive strategies that quantify the 'T cell pool that matters' rather than the total T cell infiltrate. In parallel work in which we have examined intratumoral T cell function we have demonstrated how activated T cells influence tumor cells located many cell layers away, resulting in the concept of 'cytokine sensing' in tumor tissue. Finally, we have identified a druggable regulator of the CD47 checkpoint that holds back the activity of myeloid cells in tumor micro-environments.
Next to the output of this project with respect to the biological knowledge obtained, this project has yielded a number of novel technologies to characterize immune activity in the tumor microenvironment and at tissue sites in more general. These technologies include 1. a novel approach to measure and characterize spatial heterogeneity in cancers through user defined uncaging of antibody tags, 2. an ex vivo human tumor fragment system to describe how intratumoral immune responses are reactivated by immune checkpoint blockade, and 3. a technology to characterize the antigen specificity of T cell pools or TCRs of interest in a high-throughput and HLA-unbiased fashion.
The research carried out in this project has been shared through academic publications and presentations. Furthermore, we have actively promoted the adoption of the technologies that we have developed by other research groups both locally and internationally. Finally, the development of inhibitors of the CD47 checkpoint regulator that we identified in this project is currently being pursued in biotech.
