A tumor-immune interaction model for hepatocellular carcinoma based on measured lymphocyte counts in patients undergoing radiotherapy

Radiother Oncol. 2020 Oct;151:73-81. doi: 10.1016/j.radonc.2020.07.025. Epub 2020 Jul 15.

Abstract

Purpose: The impact of radiation therapy on the immune system has recently gained attention particularly when delivered in combination with immunotherapy. However, it is unclear how different treatment fractionation regimens influence the interaction between the immune system and radiation. The goal of this work was to develop a mathematical model that quantifies both the immune stimulating as well as the immunosuppressive effects of radiotherapy and simulates the effects of different fractionation regimens based on patient data.

Methods and materials: The framework describes the temporal evolution of tumor cells, lymphocytes, and inactivated dying tumor cells releasing antigens during radiation therapy, specifically modeling how recruited lymphocytes inhibit tumor progression. The parameters of the model were partly taken from the literature and in part extracted from blood samples (circulating lymphocytes: CLs) collected from hepatocellular carcinoma patients undergoing radiotherapy and their outcomes. The dose volume histograms to circulating lymphocytes were calculated with a probability-based model.

Results: Based on the fitted parameters, the model enabled a study into the depletion and recovery of CLs in patients as a function of fractionation regimen. Our results quantify the ability of short fractionation regimens to lead to shorter periods of lymphocyte depletion and predict faster recovery after the end of treatment. The model shows that treatment breaks between fractions can prolong the period of lymphocyte depletion and should be avoided.

Conclusions: This study introduces a mathematical model for tumor-immune interactions using clinically extracted radiotherapy patient data, which can be applied to design trials aimed at minimizing lymphocyte depleting effects in radiation therapy.

Keywords: Clinical trials; Immune checkpoint inhibitor; Lymphocyte depletion; Mathematical modeling; Radiation therapy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Carcinoma, Hepatocellular* / radiotherapy
  • Humans
  • Liver Neoplasms* / radiotherapy
  • Lymphocyte Count
  • Lymphocytes
  • Models, Theoretical