Loading...

Distinct dynamics of migratory response to pd-1 and ctla-4 blockade reveals new mechanistic insights for potential t-cell reinvigoration following immune checkpoint blockade

Safaeifard, F ; Sharif University of Technology | 2022

327 Viewed
  1. Type of Document: Article
  2. DOI: 10.3390/cells11223534
  3. Publisher: MDPI , 2022
  4. Abstract:
  5. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1), two clinically relevant targets for the immunotherapy of cancer, are negative regulators of T-cell activation and migration. Optimizing the therapeutic response to CTLA-4 and PD-1 blockade calls for a more comprehensive insight into the coordinated function of these immune regulators. Mathematical modeling can be used to elucidate nonlinear tumor–immune interactions and highlight the underlying mechanisms to tackle the problem. Here, we investigated and statistically characterized the dynamics of T-cell migration as a measure of the functional response to these pathways. We used a previously developed three-dimensional organotypic culture of patient-derived tumor spheroids treated with anti-CTLA-4 and anti-PD-1 antibodies for this purpose. Experiment-based dynamical modeling revealed the delayed kinetics of PD-1 activation, which originates from the distinct characteristics of PD-1 and CTLA-4 regulation, and followed through with the modification of their contributions to immune modulation. The simulation results show good agreement with the tumor cell reduction and active immune cell count in each experiment. Our findings demonstrate that while PD-1 activation provokes a more exhaustive intracellular cascade within a mature tumor environment, the time-delayed kinetics of PD-1 activation outweighs its preeminence at the individual cell level and consequently confers a functional dominance to the CTLA-4 checkpoint. The proposed model explains the distinct immunostimulatory pattern of PD-1 and CTLA-4 blockade based on mechanisms involved in the regulation of their expression and may be useful for planning effective treatment schemes targeting PD-1 and CTLA-4 functions. © 2022 by the authors
  6. Keywords:
  7. Delayed dynamics ; Heterogeneous random walks ; Immune checkpoint blockade ; Organotypic tumor culture ; T-cell migration ; Tumor–immune interaction ; Collagen ; Immune checkpoint inhibitor ; Ipilimumab ; Nivolumab ; Programmed death 1 ligand 1 ; Programmed death 1 receptor ; Cytotoxic T lymphocyte antigen 4 ; Algorithm ; Cancer immunotherapy ; CD8+ T lymphocyte ; Cell death ; Cell migration ; Cytotoxicity ; Gene expression ; Human ; Immunomodulation ; Leukocyte count ; Lymphocyte ; Protein expression ; Thyroid tumor ; Tumor associated leukocyte ; Tumor immunity ; Tumor microenvironment ; Tumor spheroid ; Tumor volume ; Metabolism ; Neoplasm ; Pathology ; Procedures ; T lymphocyte ; Abatacept ; CTLA-4 Antigen ; Humans ; Immune Checkpoint Inhibitors ; Immunotherapy ; Neoplasms ; T-Lymphocytes
  8. Source: Cells ; Volume 11, Issue 22 , 2022 ; 20734409 (ISSN)
  9. URL: https://www.mdpi.com/2073-4409/11/22/3534