TY - JOUR
T1 - Kinetics of Intratumoral Immune Cell Activation During Chemoradiation for Cervical Cancer
AU - Dorta-Estremera, Stephanie
AU - Colbert, Lauren E.
AU - Nookala, Sita S.
AU - Yanamandra, Ananta V.
AU - Yang, Guojun
AU - Delgado, Andrea
AU - Mikkelson, Megan
AU - Eifel, Patricia J
AU - Jhingran, Anuja
AU - Lilie, Lin L.
AU - Welsh, James
AU - Schmeler, Kathleen
AU - Sastry, Jagannadha K.
AU - Klopp, Ann
N1 - Funding Information:
This study was funded by The University of Texas MD Anderson Cancer Center HPV-related Cancers Moonshot. The Flow Cytometry Core at MD Anderson Cancer Center is supported by the Cancer Center Support Grant NCI# P30 CA16672.
Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/11/1
Y1 - 2018/11/1
N2 - Purpose: Radiation therapy has direct cytotoxic effects on tumor-infiltrating lymphocytes, but it also has immune stimulatory effects that increase immune cell infiltration. The dynamics of these competing effects on immune cells at the site of the tumor are poorly characterized during chemoradiation treatment (CRT) because of the difficulty of obtaining consecutive tumor biopsies. We used a minimally invasive cervical cytobrushing method to analyze the kinetics of intratumoral immune cell changes in patients with cervical cancer during CRT. Methods and Materials: Cervical brushings were obtained from 20 patients with cervical cancer at baseline and during fractionated radiation therapy and cisplatin (weeks 1, 3, and 5). Matching peripheral blood mononuclear cells were obtained from 9 patients at the same time points. Cells were analyzed using multispectral flow cytometry to identify T cell and myeloid cell subsets and their activation status. Changes in immune cell subsets throughout treatment were calculated using matched-pair analysis with Wilcoxon rank sum test. Results: We observed a significant decline in CD3+ total T cells, as well as CD8+ and CD4+ T-cell subsets in the first week of treatment from baseline, followed by variable expansion at weeks 3 and 5. This coincided with higher levels of proliferating CD8+ T cells expressing Ki67 at week 3 of treatment. The percentages of activated CD8+ T cells expressing CD69 continuously increased over the course of treatment, whereas the percentage of activated CD11c+CD11b– dendritic cells was highest during the first week. Many of these changes were not observed in the blood. Conclusions: Our results identified immune dynamic changes during CRT, indicating that CRT may be immune activating at the site of the tumor. This study also suggests the importance of sequential analyses of the local tumor microenvironment in addition to peripheral blood.
AB - Purpose: Radiation therapy has direct cytotoxic effects on tumor-infiltrating lymphocytes, but it also has immune stimulatory effects that increase immune cell infiltration. The dynamics of these competing effects on immune cells at the site of the tumor are poorly characterized during chemoradiation treatment (CRT) because of the difficulty of obtaining consecutive tumor biopsies. We used a minimally invasive cervical cytobrushing method to analyze the kinetics of intratumoral immune cell changes in patients with cervical cancer during CRT. Methods and Materials: Cervical brushings were obtained from 20 patients with cervical cancer at baseline and during fractionated radiation therapy and cisplatin (weeks 1, 3, and 5). Matching peripheral blood mononuclear cells were obtained from 9 patients at the same time points. Cells were analyzed using multispectral flow cytometry to identify T cell and myeloid cell subsets and their activation status. Changes in immune cell subsets throughout treatment were calculated using matched-pair analysis with Wilcoxon rank sum test. Results: We observed a significant decline in CD3+ total T cells, as well as CD8+ and CD4+ T-cell subsets in the first week of treatment from baseline, followed by variable expansion at weeks 3 and 5. This coincided with higher levels of proliferating CD8+ T cells expressing Ki67 at week 3 of treatment. The percentages of activated CD8+ T cells expressing CD69 continuously increased over the course of treatment, whereas the percentage of activated CD11c+CD11b– dendritic cells was highest during the first week. Many of these changes were not observed in the blood. Conclusions: Our results identified immune dynamic changes during CRT, indicating that CRT may be immune activating at the site of the tumor. This study also suggests the importance of sequential analyses of the local tumor microenvironment in addition to peripheral blood.
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U2 - 10.1016/j.ijrobp.2018.06.404
DO - 10.1016/j.ijrobp.2018.06.404
M3 - Article
C2 - 30017792
AN - SCOPUS:85053202041
SN - 0360-3016
VL - 102
SP - 593
EP - 600
JO - International Journal of Radiation Oncology Biology Physics
JF - International Journal of Radiation Oncology Biology Physics
IS - 3
ER -