Delayed dynamics of migratory response to CTLA-4 blockade reveals a mechanistic view on potential T cells reinvigoration following immune checkpoint blockade

• Published in: bioRxiv
• Main Authors: Safaeifard, Fateme, Seyed Peyman Shariatpanahi, Golieai, Bahram, Aref, Amir Reza, Mohammad-Hadi Foroughmand-Araabi, Sama Goliaei, Ruegg, Curzio
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 05.04.2022
• Subjects: Apoptosis; Cell activation; Cell culture; Cell death; CTLA-4 protein; Cytotoxicity; Immune checkpoint; Immunogenicity; Immunomodulation; Immunotherapy; Leukocyte migration; Lymphocytes T; PD-1 protein; Spheroids; Tumor cells; Tumor microenvironment
• DOI: 10.1101/2022.04.03.485914

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) receptors, two clinically relevant targets for immunotherapy of cancer, are negative regulators of in immune cell activation and migration. However, optimizing therapeutic outcomes still requires fundamental research to reach a comprehensive insight into the coherent function of immune regulators. Here, we investigated the statistical dynamics of T cells migration as a measure of the functional response to these pathways in an experimental setup of immune checkpoint blockade. For this purpose, we used a previously developed 3-dimensional organotypic culture of patient-derived tumor spheroids. Experiment-based dynamical modeling remarked distinct characteristics of the receptors regulation followed through with the modification of their proportions in the immune modulation. We demonstrated that time-delayed kinetics of PD-1 activation just overrides its relatively more efficient cell-level function which potentially makes an operative contribution to the functional dominance of CTLA-4 in the tumor microenvironment. Simulation results showed good agreement with data for tumor cells reduction and active immune cells count observed in each experiment. These analyses propose a new mechanistic view on relative immunogenicity of PD-1 and CTLA-4 inhibitors manifested in literature and point the possible inherent obstacles in checkpoint inhibition-based immunotherapy of cancer to address in the future. Significance: Ex vivo monitoring of temporal response to PD-1 and CTLA-4 in the closure of T cell movement dynamics and elucidating their feasible commitment to the kinetic constraints at cell-level resolution. Delayed dynamics of migratory response to CTLA-4 inhibition revealed a mechanistic view on potential T cell reinvigoration following immune checkpoint blockade. Competing Interest Statement The authors have declared no competing interest. Footnotes * https://github.com/safaeifard/F-Safaeifard/tree/main/Heterogenous%20AR-1%20Model