Molecular mechanisms underlying the modulation of T-cell proliferation and cytotoxicity by immobilized CCL21 and ICAM1

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Abstract Background Adoptive cancer immunotherapy, using engineered T-cells, expressing chimeric antigen receptor (CARs) or autologous tumor infiltrating lymphocytes (TILs) became, in recent years, a major therapeutic approach for diverse types of cancer. However, despite the transformative potential of adoptive cancer immunotherapy, this field still faces a major challenge manifested by the complex interplay between the proliferation rate and cytotoxic capacity of effector CD8 + T cells. Methods We performed integrated analysis of specific differentiation markers via flow cytometry, together with gene expression profiling to explore the molecular mechanisms through which a “synthetic immune niche” (SIN), composed of immobilized CCL21 and ICAM1, modulates the interplay between the proliferation and cytotoxic potency of effector CD8 + T cells. Results On day 3, the transcriptomic effect induced by the SIN was largely similar for both DC/OVA and anti CD3/CD28-activated cells. Cell proliferation increased and the cells exhibited high killing capacity. On day 4 and on, the proliferation/cytotoxicity phenotypes were radically “activation-specific”; The DC/OVA-activated cells lost their cytotoxic activity, which, in turn, was rescued by the SIN treatment. Upon longer incubation, the cytotoxic activity further declined, and on day7, could not be rescued by the SIN. SIN stimulation following activation with antiCD3/CD28 beads resulted in a highly proliferative phenotype with low cytotoxicity, yet the cells regained killing activity on day 7. Potential molecular regulations of the SIN effects were identified, based on transcriptomic and multispectral imaging profiling. Conclusions These data indicate that cell proliferation and cytotoxicity are negatively correlated, and the interplay between them is differentially regulated by the mode of initial activation. The SIN stimulation greatly enhanced the cell expansion, following both activation modes, while maintaining high cytotoxic potency, suggesting that it could reinforce adoptive cancer immunotherapy.

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