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Sensitivity of human tumors to T cell attack

Periodic Reporting for period 1 - SENSIT (Sensitivity of human tumors to T cell attack)

Reporting period: 2017-12-01 to 2019-05-31

The goal of this project is to determine which parameters control the sensitivity of human tumors to attack by the T cell-based immune system. We address this central question in cancer immunology/ cancer immunotherapy through 3 complementary approaches.
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.
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 phenotypic 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. In parallel work 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.
Within this project we aim to characterize the interaction between immune cells, and in particular the T cell-based immune system, and human cancers. The insights coming out of this work help explain the activity of current cancer immunotherapies in only a subset of human cancers and provide leads for the development of novel immunotherapeutic interventions.