Dysfunctional Immune Synapses in T Cell Immunodeficiencies

Abstract Understanding how the immune system in patients with cancer interacts with malignant cells is critical for the development of successful immunotherapeutic strategies. We studied peripheral blood from newly diagnosed patients with acute myeloid leukemia (AML) to assess the impact of this disease on the patients' T cells. The absolute number of peripheral blood T cells is increased in AML compared with healthy controls. An increase in the absolute number of CD3+56+ cells was also noted. Gene expression profiling on T cells from AML patients compared with healthy donors demonstrated global differences in transcription suggesting aberrant T-cell activation patterns. These gene expression changes differ from those observed in chronic lymphocytic leukemia (CLL), indicating the heterogeneous means by which different tumors evade the host immune response. However, in common with CLL, differentially regulated genes involved in actin cytoskeletal formation were identified, and therefore the ability of T cells from AML patients to form immunologic synapses was assessed. Although AML T cells could form conjugates with autologous blasts, their ability to form immune synapses and recruit phosphotyrosine signaling molecules to the synapse was significantly impaired. These findings identify T-cell dysfunction in AML that may contribute to the failure of a host immune response against leukemic blasts.

Download Full-text

Immune synapses in T-cell activation

Current Opinion in Immunology ◽

10.1016/j.coi.2006.03.011 ◽

2006 ◽

Vol 18 (3) ◽

pp. 298-304 ◽

Cited By ~ 87

Author(s):

Sašo Čemerski ◽

Andrey Shaw

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Immune Synapses

Download Full-text

Leveraging a physiologically based quantitative translational modeling platform for designing bispecific T cell engagers for treatment of multiple myeloma

10.1101/2021.12.06.471352 ◽

2021 ◽

Author(s):

Tomoki Yoneyama ◽

Mi-Sook Kim ◽

Konstantin Piatkov ◽

Haiqing Wang ◽

Andy Z.X. Zhu

Keyword(s):

Multiple Myeloma ◽

T Cells ◽

T Cell ◽

Tumor Cell ◽

Tumor Cells ◽

Synapse Formation ◽

Modeling Framework ◽

Immune Synapse ◽

Immune Synapses ◽

Physiologically Based

Bispecific T cell engager (TCE) is an emerging anti-cancer modality which redirects cytotoxic T cells to tumor cells expressing tumor-associated antigen (TAA) thereby forming immune synapses to exerts anti-tumor effects. Considering the protein engineering challenges in designing and optimizing size and pharmacokinetically acceptable TCEs in the context of the complexity of intercellular bridging between T cells and tumor cells, a physiologically relevant and clinically verified computational modeling framework is of crucial importance to guide the process to understand the protein engineering trade offs. In this study, we developed a quantitative, physiologically based computational framework to predict immune synapse formation for a variety of molecular format of TCEs in tumor tissue. Our model incorporated the molecular size dependent biodistribution using the two pore theory, extra-vascularization of T cells and hematologic cancer cells, mechanistic bispecific intercellular binding of TCEs and competitive inhibitory interaction by shed targets. The biodistribution of TCE was verified by positron emission tomography imaging of [89Zr]AMG211 (a carcinoembryonic antigen-targeting TCE) in patients. Parameter sensitivity analyses indicated that immune synapse formation was highly sensitive to TAA expression, degree of target shedding and binding selectivity to tumor cell surface TAA over shed target. Interestingly, the model suggested a “sweet spot” for TCE’s CD3 binding affinity which balanced the trapping of TCE in T cell rich organs. The final model simulations indicated that the number of immune synapses is similar (~50/tumor cell) between two distinct clinical stage B cell maturation antigen (BCMA)-targeting TCEs, PF-06863135 in IgG format and AMG420 in BiTE format, at their respective efficacious dose in multiple myeloma patients, demonstrating the applicability of the developed computational modeling framework to molecular design optimization and clinical benchmarking for TCEs. This framework can be employed to other targets to provide a quantitative means to facilitate the model-informed best in class TCE discovery and development.

Download Full-text

Dendritic cell ICAM-1 strengthens immune synapses but is dispensable for effector and memory responses

10.1101/2021.10.27.466043 ◽

2021 ◽

Author(s):

Anita Sapoznikov ◽

Stav Kozlovski ◽

Sara W. Feigelson ◽

Natalia Davidzohn ◽

Noa Wigoda ◽

...

Keyword(s):

T Cell ◽

Cytotoxic T Cells ◽

Cd8 T Cell ◽

Cell Proliferation And Differentiation ◽

Immune Synapses ◽

Proliferation And Differentiation ◽

Skin Response ◽

Memory Lymphocytes

Lymphocyte priming in lymph nodes (LNs) depends on the formation of functional TCR specific immune synapses (ISs) with antigen (Ag) presenting dendritic cells. The high affinity LFA-1 ligand ICAM-1 has been implicated in different ISs studied in vitro. The in vivo roles of DC ICAM-1 in Ag stimulated T cell differentiation have been unclear. In newly generated DC conditional ICAM-1 knockout mice, we report that under Th1 polarizing conditions, ICAM-1 deficient DCs could not engage in stable conjugates with newly generated CD8 blasts. Nevertheless, these DCs triggered normal lymphocyte priming, proliferation and differentiation into functional cytotoxic T cells (CTLs) and central memory lymphocytes (Tcm) in both vaccinated and virus infected skin. Single cell RNAseq analysis confirmed that Tcm were normally generated in these mice and gave rise to normal T effectors during a recall skin response. Our results suggest that although CD8 T cell blasts tightly bind DC-ICAM-1, strongly adhesive DC-T ISs are not necessary for functional TCR dependent DC mediated CD8 T cell proliferation and differentiation into productive effector and memory lymphocytes.

Download Full-text