TIGIT expressing CD4+T cells represent a tumor-supportive T cell subset in chronic lymphocytic leukemia

While research on T cell exhaustion in context of cancer particularly focuses on CD8C cytotoxic T cells, the role of inhibitory receptors on CD4C T-helper cells have remained largely unexplored. TIGIT is a recently identified inhibitory receptor on T cells and natural killer (NK) cells. In this study, we examined TIGIT expression on T cell subsets from CLL patients. While we did not observe any differences in TIGIT expression in CD8C T cells of healthy controls and CLL cells, we found an enrichment of TIGITC T cells in the CD4C T cell compartment in CLL. Intriguingly, CLL patients with an advanced disease stage displayed elevated numbers of CD4C TIGITC T cells compared to low risk patients. Autologous CLL-T cell co-culture assays revealed that depleting CD4C TIGITC expressing T cells from co-cultures significantly decreased CLL viability. Accordingly, a supportive effect of TIGITCCD4C T cells on CLL cells in vitro could be recapitulated by blocking the interaction of TIGIT with its ligands using TIGIT-Fc molecules, which also impeded the T cell specific production of CLL-prosurvival cytokines. Our data reveal that TIGITCCD4CT cells provide a supportive microenvironment for CLL cells, representing a potential therapeutic target for CLL treatment

Exome sequencing of the TCL1 mouse model for CLL reveals genetic heterogeneity and dynamics during disease development

The TCL1 mouse model is widely used to study pathophysiology, clonal evolution and drug sensitivity or resistance of chronic lymphocytic leukemia (CLL). By performing whole exome sequencing, we present the genetic landscape of primary tumors from TCL1 mice and of TCL1 tumors serially transplanted into wildtype recipients to mimic clonal evolution. We show that similar to CLL patients, mutations in mice are frequently subclonal and heterogenous among different primary TCL1 mice. We further describe that this molecular heterogeneity mirrors heterogenous disease characteristics such as organ infiltration or CLL dependent T cell skewing. Similar to human CLL, we further observed the occurrence of novel mutations and structural variations during clonal evolution and found plasticity in the expansion of B cell receptor specific subclones. Thus, our results uncover that the genetic complexity, pathway dependence and clonal dynamics in mouse CLL are in relevant agreement to human CLL, and they are important to consider in future research using the TCL1 mouse for studying CLL