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Sensitivity of human tumors to T cell attack

Periodic Reporting for period 4 - SENSIT (Sensitivity of human tumors to T cell attack)

Reporting period: 2022-06-01 to 2022-11-30

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 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.
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.
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