PD-1 restrains radiotherapy-induced abscopal effect

Sean S Park, Haidong M Dong, Xin Liu, Susan M. Harrington, Christopher J. Krco, Michael P. Grams, Aaron Mansfield, Keith M. Furutani, Kenneth R. Olivier, Eugene D Kwon

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Abstract

We investigated the influence of PD-1 expression on the systemic antitumor response (abscopal effect) induced by stereotactic ablative radiotherapy (SABR) in preclinical melanoma and renal cell carcinoma models. We compared the SABRinduced antitumor response in PD-1-expressing wild-type (WT) and PD-1-deficient knockout (KO) mice and found that PD-1 expression compromises the survival of tumor-bearing mice treated with SABR. None of the PD-1 WT mice survived beyond 25 days, whereas 20% of the PD-1 KO mice survived beyond 40 days. Similarly, PD-1-blocking antibody in WT mice was able to recapitulate SABR-induced antitumor responses observed in PD-1 KO mice and led to increased survival. The combination of SABR plus PD-1 blockade induced near complete regression of the irradiated primary tumor (synergistic effect), as opposed to SABR alone or SABR plus control antibody. The combination of SABR plus PD-1 blockade therapy elicited a 66% reduction in size of nonirradiated, secondary tumors outside the SABR radiation field (abscopal effect). The observed abscopal effect was tumor specific and was not dependent on tumor histology or host genetic background. The CD11ahigh CD8+ T-cell phenotype identifies a tumor-reactive population, which was associated in frequency and function with a SABR-induced antitumor immune response in PD-1 KO mice. We conclude that SABR induces an abscopal tumorspecific immune response in both the irradiated and nonirradiated tumors, which is potentiated by PD-1 blockade. The combination of SABR and PD-1 blockade has the potential to translate into a potent immunotherapy strategy in the management of patients with metastatic cancer.

Original languageEnglish (US)
Pages (from-to)610-619
Number of pages10
JournalCancer immunology research
Volume3
Issue number6
DOIs
StatePublished - Jun 1 2015

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Radiotherapy
Knockout Mice
Neoplasms
Blocking Antibodies
Renal Cell Carcinoma
Immunotherapy
Melanoma
Histology
Radiation
T-Lymphocytes
Phenotype
Survival
Antibodies
Population

ASJC Scopus subject areas

  • Cancer Research
  • Immunology

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PD-1 restrains radiotherapy-induced abscopal effect. / Park, Sean S; Dong, Haidong M; Liu, Xin; Harrington, Susan M.; Krco, Christopher J.; Grams, Michael P.; Mansfield, Aaron; Furutani, Keith M.; Olivier, Kenneth R.; Kwon, Eugene D.

In: Cancer immunology research, Vol. 3, No. 6, 01.06.2015, p. 610-619.

Research output: Contribution to journalArticle

Park, SS, Dong, HM, Liu, X, Harrington, SM, Krco, CJ, Grams, MP, Mansfield, A, Furutani, KM, Olivier, KR & Kwon, ED 2015, 'PD-1 restrains radiotherapy-induced abscopal effect', Cancer immunology research, vol. 3, no. 6, pp. 610-619. https://doi.org/10.1158/2326-6066.CIR-14-0138
Park, Sean S ; Dong, Haidong M ; Liu, Xin ; Harrington, Susan M. ; Krco, Christopher J. ; Grams, Michael P. ; Mansfield, Aaron ; Furutani, Keith M. ; Olivier, Kenneth R. ; Kwon, Eugene D. / PD-1 restrains radiotherapy-induced abscopal effect. In: Cancer immunology research. 2015 ; Vol. 3, No. 6. pp. 610-619.
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AU - Liu, Xin

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AU - Grams, Michael P.

AU - Mansfield, Aaron

AU - Furutani, Keith M.

AU - Olivier, Kenneth R.

AU - Kwon, Eugene D

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