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 Zaorsky, Xinliang Ma, Yajing Wang, Adam P. Dicker, Bo Lu

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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
Volume13
Issue number4
DOIs
StatePublished - Apr 1 2018

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Cytotoxic T-Lymphocytes
Radiotherapy
Radiation
Mortality
Lung Neoplasms
Thorax
CD8-Positive T-Lymphocytes
Myocarditis
Hodgkin Disease
Stroke Volume
Anti-Idiotypic Antibodies
Immunoglobulin G
Cardiotoxicity
Clinical Trials
Breast Neoplasms
Lung
Antibodies
Therapeutics
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

Du, S., Zhou, L., Alexander, G. S., Park, K., Yang, L., Wang, N., ... Lu, B. (2018). PD-1 Modulates Radiation-Induced Cardiac Toxicity through Cytotoxic T Lymphocytes. Journal of Thoracic Oncology, 13(4), 510-520. https://doi.org/10.1016/j.jtho.2017.12.002
Du, Shisuo ; Zhou, Lin ; Alexander, Gregory S. ; Park, Kyewon ; Yang, Lifeng ; Wang, Nadan ; Zaorsky, Nicholas ; Ma, Xinliang ; Wang, Yajing ; Dicker, Adam P. ; Lu, Bo. / PD-1 Modulates Radiation-Induced Cardiac Toxicity through Cytotoxic T Lymphocytes. In: Journal of Thoracic Oncology. 2018 ; Vol. 13, No. 4. pp. 510-520.
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Du, S, Zhou, L, Alexander, GS, Park, K, Yang, L, Wang, N, Zaorsky, N, Ma, X, Wang, Y, Dicker, AP & Lu, B 2018, 'PD-1 Modulates Radiation-Induced Cardiac Toxicity through Cytotoxic T Lymphocytes', Journal of Thoracic Oncology, vol. 13, no. 4, pp. 510-520. https://doi.org/10.1016/j.jtho.2017.12.002

PD-1 Modulates Radiation-Induced Cardiac Toxicity through Cytotoxic T Lymphocytes. / Du, Shisuo; Zhou, Lin; Alexander, Gregory S.; Park, Kyewon; Yang, Lifeng; Wang, Nadan; Zaorsky, Nicholas; Ma, Xinliang; Wang, Yajing; Dicker, Adam P.; Lu, Bo.

In: Journal of Thoracic Oncology, Vol. 13, No. 4, 01.04.2018, p. 510-520.

Research output: Contribution to journalArticle

TY - JOUR

T1 - PD-1 Modulates Radiation-Induced Cardiac Toxicity through Cytotoxic T Lymphocytes

AU - Du, Shisuo

AU - Zhou, Lin

AU - Alexander, Gregory S.

AU - Park, Kyewon

AU - Yang, Lifeng

AU - Wang, Nadan

AU - Zaorsky, Nicholas

AU - Ma, Xinliang

AU - Wang, Yajing

AU - Dicker, Adam P.

AU - Lu, Bo

PY - 2018/4/1

Y1 - 2018/4/1

N2 - 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.

AB - 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.

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