PD-1 Modulates Radiation-Induced Cardiac Toxicity through Cytotoxic T Lymphocytes

Shisuo Du, Lin Zhou, Gregory S. Alexander, Kyewon Park, Lifeng Yang, Nadan Wang, Nicholas G. Zaorsky, Xinliang Ma, Yajing Wang, Adam P. Dicker, Bo Lu

Research output: Contribution to journalArticlepeer-review

71 Scopus citations


Introduction: Combined immune checkpoint blockade has led to rare autoimmune complications, such as fatal myocarditis. Recent approvals of several anti–programmed death 1 (anti–PD-1) drugs for lung cancer treatment prompted ongoing clinical trials that directly combine PD-1 inhibitors with thoracic radiotherapy for locally advanced lung cancer. Overlapping toxicities from either modality have the potential to increase the risk for radiation-induced cardiotoxicity (RICT), which is well documented among patients with Hodgkin's disease and breast cancer. Methods: To investigate cardiotoxicity without the compounding pulmonary toxicity from thoracic radiotherapy, we developed a technique to deliver cardiac irradiation (CIR) in a mouse model concurrently with PD-1 blockade to determine the presence of cardiac toxicity by using physiological testing and mortality as end points along with histological analysis. Results: We observed an acute mortality of 30% within 2 weeks after CIR plus anti–PD-1 antibody compared with 0% from CIR plus immunoglobulin G (p = 0.023). Physiological testing demonstrated a reduced left ventricular ejection fraction (p < 0.01) by echocardiogram. Tissue analyses revealed increased immune cell infiltrates within cardiac tissue. Depletion of CD8-positive lymphocytes with anti-CD8 antibody reversed the acute mortality, suggesting that the toxicity is CD8-positive cell–mediated. To validate these findings using a clinically relevant fractionated radiotherapy regimen, we repeated the study by delivering five daily fractions of 6 Gy. Similar mortality, cardiac dysfunction, and histological changes were observed in mice receiving fractionated radiotherapy with concurrent anti–PD-1 therapy. Conclusions: This study provides strong preclinical evidence that radiation-induced cardiotoxicity is modulated by the PD-1 axis and that PD-1 blockade should be administered with careful radiotherapy planning with an effort of reducing cardiac dose.

Original languageEnglish (US)
Pages (from-to)510-520
Number of pages11
JournalJournal of Thoracic Oncology
Issue number4
StatePublished - Apr 2018

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pulmonary and Respiratory Medicine


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