Stereotactic Ablative Radiation Therapy Induces Systemic Differences in Peripheral Blood Immunophenotype Dependent on Irradiated Site

Heather M. McGee, Megan E Daly, Sohelia Azghadi, Susan L Stewart, Leslie Oesterich, Jeffrey Schlom, Renee Donahue, Jonathan D. Schoenfeld, Qian Chen, Shyam Rao, Ruben C Fragoso, Richard K Valicenti, Robert J Canter, Emanual Michael Maverakis, William J Murphy, Karen Kelly, Arta M Monjazeb

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Abstract

Purpose: Despite the strong interest in combining stereotactic ablative radiation therapy (SAR) with immunotherapy, limited data characterizing the systemic immune response after SAR are available. We hypothesized that the systemic immune response to SAR would differ by irradiated site owing to inherent differences in the microenvironment of various organs. Methods and Materials: Patients receiving SAR to any organ underwent prospective blood banking before and 1 to 2 weeks after SAR. Peripheral blood mononuclear cells (PBMCs) and serum were isolated. PBMCs were stained with fluorophore-conjugated antibodies against T and natural killer (NK) cell markers. Cells were interrogated by flow cytometry, and the results were analyzed using FlowJo software. Serum cytokine and chemokine levels were measured using Luminex. We analyzed the changes from before to after therapy using paired t tests or 1-way analysis of variance (ANOVA) with Bonferroni's post-test. Results: A total of 31 patients had evaluable PBMCs for flow cytometry and 37 had evaluable serum samples for Luminex analysis. The total number of NK cells and cytotoxic (CD56dimCD16+) NK cells decreased (P =.02) and T-cell immunoglobulin- and mucin domain–containing molecule-3–positive (TIM3+) NK cells increased (P =.04) after SAR to parenchymal sites (lung and liver) but not to bone or brain. The total memory CD4+ T cells, activated inducible co-stimulator–positive and CD25+CD4+ memory T cells, and activated CD25+CD8+ memory T cells increased after SAR to parenchymal sites but not bone or brain. The circulating levels of tumor necrosis factor-α (P =.04) and multiple chemokines, including RANTES (P =.04), decreased after SAR to parenchymal sites but not bone or brain. Conclusions: Our data suggest SAR to parenchymal sites induces systemic immune changes, including a decrease in total and cytotoxic NK cells, an increase in TIM3+ NK cells, and an increase in activated memory CD4+ and CD8+ T cells. SAR to nonparenchymal sites did not induce these changes. By comparing the immune response after radiation to different organs, our data suggest SAR induces systemic immunologic changes that are dependent on the irradiated site.

Original languageEnglish (US)
JournalInternational Journal of Radiation Oncology Biology Physics
DOIs
StateAccepted/In press - Jan 1 2018

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blood
radiation therapy
Radiotherapy
Natural Killer Cells
blood cells
cells
T-Lymphocytes
organs
bones
brain
Blood Cells
cytometry
Chemokines
Bone and Bones
serums
Flow Cytometry
Brain
Serum
blood serum
Chemokine CCL5

ASJC Scopus subject areas

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

Cite this

@article{d1e4e9702203469faaf53afac1ea5761,
title = "Stereotactic Ablative Radiation Therapy Induces Systemic Differences in Peripheral Blood Immunophenotype Dependent on Irradiated Site",
abstract = "Purpose: Despite the strong interest in combining stereotactic ablative radiation therapy (SAR) with immunotherapy, limited data characterizing the systemic immune response after SAR are available. We hypothesized that the systemic immune response to SAR would differ by irradiated site owing to inherent differences in the microenvironment of various organs. Methods and Materials: Patients receiving SAR to any organ underwent prospective blood banking before and 1 to 2 weeks after SAR. Peripheral blood mononuclear cells (PBMCs) and serum were isolated. PBMCs were stained with fluorophore-conjugated antibodies against T and natural killer (NK) cell markers. Cells were interrogated by flow cytometry, and the results were analyzed using FlowJo software. Serum cytokine and chemokine levels were measured using Luminex. We analyzed the changes from before to after therapy using paired t tests or 1-way analysis of variance (ANOVA) with Bonferroni's post-test. Results: A total of 31 patients had evaluable PBMCs for flow cytometry and 37 had evaluable serum samples for Luminex analysis. The total number of NK cells and cytotoxic (CD56dimCD16+) NK cells decreased (P =.02) and T-cell immunoglobulin- and mucin domain–containing molecule-3–positive (TIM3+) NK cells increased (P =.04) after SAR to parenchymal sites (lung and liver) but not to bone or brain. The total memory CD4+ T cells, activated inducible co-stimulator–positive and CD25+CD4+ memory T cells, and activated CD25+CD8+ memory T cells increased after SAR to parenchymal sites but not bone or brain. The circulating levels of tumor necrosis factor-α (P =.04) and multiple chemokines, including RANTES (P =.04), decreased after SAR to parenchymal sites but not bone or brain. Conclusions: Our data suggest SAR to parenchymal sites induces systemic immune changes, including a decrease in total and cytotoxic NK cells, an increase in TIM3+ NK cells, and an increase in activated memory CD4+ and CD8+ T cells. SAR to nonparenchymal sites did not induce these changes. By comparing the immune response after radiation to different organs, our data suggest SAR induces systemic immunologic changes that are dependent on the irradiated site.",
author = "McGee, {Heather M.} and Daly, {Megan E} and Sohelia Azghadi and Stewart, {Susan L} and Leslie Oesterich and Jeffrey Schlom and Renee Donahue and Schoenfeld, {Jonathan D.} and Qian Chen and Shyam Rao and Fragoso, {Ruben C} and Valicenti, {Richard K} and Canter, {Robert J} and Maverakis, {Emanual Michael} and Murphy, {William J} and Karen Kelly and Monjazeb, {Arta M}",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.ijrobp.2018.04.038",
language = "English (US)",
journal = "International Journal of Radiation Oncology Biology Physics",
issn = "0360-3016",
publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - Stereotactic Ablative Radiation Therapy Induces Systemic Differences in Peripheral Blood Immunophenotype Dependent on Irradiated Site

AU - McGee, Heather M.

AU - Daly, Megan E

AU - Azghadi, Sohelia

AU - Stewart, Susan L

AU - Oesterich, Leslie

AU - Schlom, Jeffrey

AU - Donahue, Renee

AU - Schoenfeld, Jonathan D.

AU - Chen, Qian

AU - Rao, Shyam

AU - Fragoso, Ruben C

AU - Valicenti, Richard K

AU - Canter, Robert J

AU - Maverakis, Emanual Michael

AU - Murphy, William J

AU - Kelly, Karen

AU - Monjazeb, Arta M

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Purpose: Despite the strong interest in combining stereotactic ablative radiation therapy (SAR) with immunotherapy, limited data characterizing the systemic immune response after SAR are available. We hypothesized that the systemic immune response to SAR would differ by irradiated site owing to inherent differences in the microenvironment of various organs. Methods and Materials: Patients receiving SAR to any organ underwent prospective blood banking before and 1 to 2 weeks after SAR. Peripheral blood mononuclear cells (PBMCs) and serum were isolated. PBMCs were stained with fluorophore-conjugated antibodies against T and natural killer (NK) cell markers. Cells were interrogated by flow cytometry, and the results were analyzed using FlowJo software. Serum cytokine and chemokine levels were measured using Luminex. We analyzed the changes from before to after therapy using paired t tests or 1-way analysis of variance (ANOVA) with Bonferroni's post-test. Results: A total of 31 patients had evaluable PBMCs for flow cytometry and 37 had evaluable serum samples for Luminex analysis. The total number of NK cells and cytotoxic (CD56dimCD16+) NK cells decreased (P =.02) and T-cell immunoglobulin- and mucin domain–containing molecule-3–positive (TIM3+) NK cells increased (P =.04) after SAR to parenchymal sites (lung and liver) but not to bone or brain. The total memory CD4+ T cells, activated inducible co-stimulator–positive and CD25+CD4+ memory T cells, and activated CD25+CD8+ memory T cells increased after SAR to parenchymal sites but not bone or brain. The circulating levels of tumor necrosis factor-α (P =.04) and multiple chemokines, including RANTES (P =.04), decreased after SAR to parenchymal sites but not bone or brain. Conclusions: Our data suggest SAR to parenchymal sites induces systemic immune changes, including a decrease in total and cytotoxic NK cells, an increase in TIM3+ NK cells, and an increase in activated memory CD4+ and CD8+ T cells. SAR to nonparenchymal sites did not induce these changes. By comparing the immune response after radiation to different organs, our data suggest SAR induces systemic immunologic changes that are dependent on the irradiated site.

AB - Purpose: Despite the strong interest in combining stereotactic ablative radiation therapy (SAR) with immunotherapy, limited data characterizing the systemic immune response after SAR are available. We hypothesized that the systemic immune response to SAR would differ by irradiated site owing to inherent differences in the microenvironment of various organs. Methods and Materials: Patients receiving SAR to any organ underwent prospective blood banking before and 1 to 2 weeks after SAR. Peripheral blood mononuclear cells (PBMCs) and serum were isolated. PBMCs were stained with fluorophore-conjugated antibodies against T and natural killer (NK) cell markers. Cells were interrogated by flow cytometry, and the results were analyzed using FlowJo software. Serum cytokine and chemokine levels were measured using Luminex. We analyzed the changes from before to after therapy using paired t tests or 1-way analysis of variance (ANOVA) with Bonferroni's post-test. Results: A total of 31 patients had evaluable PBMCs for flow cytometry and 37 had evaluable serum samples for Luminex analysis. The total number of NK cells and cytotoxic (CD56dimCD16+) NK cells decreased (P =.02) and T-cell immunoglobulin- and mucin domain–containing molecule-3–positive (TIM3+) NK cells increased (P =.04) after SAR to parenchymal sites (lung and liver) but not to bone or brain. The total memory CD4+ T cells, activated inducible co-stimulator–positive and CD25+CD4+ memory T cells, and activated CD25+CD8+ memory T cells increased after SAR to parenchymal sites but not bone or brain. The circulating levels of tumor necrosis factor-α (P =.04) and multiple chemokines, including RANTES (P =.04), decreased after SAR to parenchymal sites but not bone or brain. Conclusions: Our data suggest SAR to parenchymal sites induces systemic immune changes, including a decrease in total and cytotoxic NK cells, an increase in TIM3+ NK cells, and an increase in activated memory CD4+ and CD8+ T cells. SAR to nonparenchymal sites did not induce these changes. By comparing the immune response after radiation to different organs, our data suggest SAR induces systemic immunologic changes that are dependent on the irradiated site.

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U2 - 10.1016/j.ijrobp.2018.04.038

DO - 10.1016/j.ijrobp.2018.04.038

M3 - Article

JO - International Journal of Radiation Oncology Biology Physics

JF - International Journal of Radiation Oncology Biology Physics

SN - 0360-3016

ER -