In Vitro and In Vivo Models of CLL-T Cell Interactions: Implications for Drug Testing.

Abstract

Simple SummaryChronic lymphocytic leukemia (CLL) cells in the peripheral blood and lymphoid microenvironment display substantially different gene expression profiles and proliferative capaci-ty. It has been suggested that CLL–T-cell interactions are key pro-proliferative stimuli in immune niches. We review in vitro and in vivo model systems that mimic CLL-T-cell interactions to trigger CLL proliferation and study therapy resistance. We focus on studies describing the co-culture of leukemic cells with T cells, or supportive cell lines expressing T-cell factors, and simplified models of CLL cells’ stimulation with recombinant factors. In the second part, we summarize mouse models revealing the role of T cells in CLL biology and implications for generating patient-derived xenografts by co-transplanting leukemic cells with T cells.T cells are key components in environments that support chronic lymphocytic leukemia (CLL), activating CLL-cell proliferation and survival. Here, we review in vitro and in vivo model systems that mimic CLL–T-cell interactions, since these are critical for CLL-cell division and resistance to some types of therapy (such as DNA-damaging drugs or BH3-mimetic venetoclax). We discuss approaches for direct CLL-cell co-culture with autologous T cells, models utilizing supportive cell lines engineered to express T-cell factors (such as CD40L) or stimulating CLL cells with combinations of recombinant factors (CD40L, interleukins IL4 or IL21, INFγ) and additional B-cell receptor (BCR) activation with anti-IgM antibody. We also summarize strategies for CLL co-transplantation with autologous T cells into immunodeficient mice (NOD/SCID, NSG, NOG) to generate patient-derived xenografts (PDX) and the role of T cells in transgenic CLL mouse models based on TCL1 overexpression (Eµ-TCL1). We further discuss how these in vitro and in vivo models could be used to test drugs to uncover the effects of targeted therapies (such as inhibitors of BTK, PI3K, SYK, AKT, MEK, CDKs, BCL2, and proteasome) or chemotherapy (fludarabine and bendamustine) on CLL–T-cell interactions and CLL proliferation.