Periodic Reporting for period 2 - SENSIT (Sensitivity of human tumors to T cell attack)
Reporting period: 2019-06-01 to 2020-11-30
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.
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