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Sensitivity of human tumors to T cell attack

Periodic Reporting for period 2 - SENSIT (Sensitivity of human tumors to T cell attack)

Reporting period: 2019-06-01 to 2020-11-30

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.
In two ongoing projects we are developing technology to measure spatial heterogeneity in cancers and measure how immune activity in human cancers is reactivated by immune checkpoint blockade. With respect to the first project, we have developed technology that allows the spatially defined uncaging of antibody tags, thereby enabling the specific isolation and characterization of cells that reside at specific sites in tissue. With respect to the second project, we have developed and exploited an ex vivo human tumor fragment system to describe how intratumoral immune responses are reactivated by immune checkpoint blockade. Key findings of this work are that 1). Capacity of immune checkpoint blockade to rekindle intratumoral immune responses predicts clinical response to ICB therapy; 2). Immune reactivation by PD-1 blockade occurs at least in part through T cell reactivation; 3). Three distinct types of immunological non-responder tumors can be defined; 4). Responder tumors show baseline properties that are consistent with the presence of tertiary lymphoid structures. Based on the latter data, we have developed an increased interest in analysis of TLS at tumor sites
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. The work is characterized by its use of newly developed technologies, such as local uncaging or human tumor fragment cultures, to dissect the interaction between the human immune system and cancer.