Biophysical Model of Lymphocyte Migration to Investigate Mechanisms Contributing to Radiation-Induced Lymphocyte Depletion
Abstract
Purpose
The underlying mechanisms of radiation-induced lymphocyte depletion are not fully understood. Our goal is to determine if the observed depletion in circulating lymphocytes after radiotherapy is solely due to cell kill, or if changes in cell migration dynamics contribute.
Methods
A biophysical model was created based on experiments in Kaede transgenic mice that express a photoconvertible green fluorescent protein. Upon UV exposure using a 405nm LED light source, cells are converted to a red fluorescent protein, allowing for highly accurate and targetable cell tracking between tumor and lymph nodes. Lymphocytes in a MC38 flank tumor were either left untreated or irradiated with a single 12Gy fraction 1h post-photoconversion. Absolute numbers of both overall and photoconverted cells were evaluated in the tumor and tumor-draining lymph node (TdLN) at 24h, 48h, and 72h. Ordinary differential equations were used to mathematically model lymphocyte recirculation of CD4 and CD8 populations between the tumor, lymph nodes and peripheral organs via circulating blood and lymphatics. Transition rates between compartments were derived using BFGS parameter optimization.
Results
Our model accurately reproduced the dispersion of lymphocytes from the tumor to peripheral compartments up to 72h in untreated animals, providing baseline transition rates. Average residence times of CD4/CD8 lymphocytes prior to radiation exposure were 61/70h in the tumor and 1.2/2h in the TdLN. In irradiated animals, results showed that in addition to the 41% surviving fraction (direct cell kill), we needed to assume significant changes in lymphocyte migration from the tumor to TdLN. An increase in tumor residence times to 200/317h (CD4/CD8) was required to explain the experimental data.
Conclusion
We conclude that cell kill alone does not explain the decrease in lymphocytes in the TdLN and circulation in irradiated animals. Changes in lymphocyte migration could explain the severe depletion and swift immune recovery in radiotherapy patients.