Periodic Reporting for period 4 - SENSIT (Sensitivity of human tumors to T cell attack)
Reporting period: 2022-06-01 to 2022-11-30
1). T cell focussed: By analysis of the activation and dysfunction states of T cells that are present in human tumors through single cell sequencing we aim to determine a). which T cell states are associated with tumor recognition potential of a T cell and b). whether functional impairment of T cells can explain lack of tumor control. Furthermore, by analysis of the effect of immune checkpoint blockade in a human tumor fragment culture system that we have developed we are deciphering how individual tumors respond to therapeutic intervention and which baseline parameters predict such responsiveness.
2). Cytokine focussed: By analysis of the spreading of T cell-secreted cytokines, such as IFNg and TNFa, through the tumor micro-environment we aim to determine how T cell activation influences tumor cell fate, including the fate of bystander tumor cells that are not touched by T cells themselves.
3). Tumor cell-focussed: Through genetic screens we are identifying modulators of immune checkpoint molecules such as PD-L1 and CD47, with the aim to understand how the strength of these inhibitory signals in the tumor micro-environment is regulated
Research in these 3 broad areas is supported by the development of novel technology to measure the tumor recognition potential of large sets of T cell receptors recovered from human tumors and of organoid-based technology to measure T cell recognition of autologous human tumor tissue. Collectively, this research should contribute to an improved understanding of the critical hurdles to achieve immune-based control of human cancers, and as such contribute to the development of personalised cancer immunotherapy.
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.