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Cited by 143Cancer Immunotherapy and BiomarkersImmunotherapy and Immune ResponsesEndometrial and Cervical Cancer Treatments

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Impact of (chemo)radiotherapy on immune cell composition and function in cervical cancer patients

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van Meir, H., Nout, R. A., Welters, M. J. P., Loof, N. M., de Kam, M. L., van Ham, J. J., Samuels, S., Kenter, G. G., Cohen, A. F., Melief, C. J. M., Burggraaf, J., van Poelgeest, M. I. E., van der Burg, S. H.·2017·OncoImmunology
DOI 10.1080/2162402x.2016.1267095PMC PMC5353924
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Abstract

New treatments based on combinations of standard therapeutic modalities and immunotherapy are of potential use, but require a profound understanding of immune modulatory properties of standard therapies. Here, the impact of standard (chemo)radiotherapy on the immune system of cervical cancer patients was evaluated. Thirty patients with cervical cancer were treated with external beam radiation therapy (EBRT), using conventional three-dimensional or intensity modulated radiation therapy without constraints for bone marrow sparing. Serial blood sampling for immunomonitoring was performed before, midway and at 3, 6 and 9 weeks after EBRT to analyze the composition of lymphocyte and myeloid-cell populations, the expression of co-stimulatory molecules, T-cell reactivity and antigen presenting cell (APC) function. Therapy significantly decreased the absolute numbers of circulating leukocytes and lymphocytes. Furthermore, the capacity of the remaining T cells to respond to antigenic or mitogenic stimulation was impaired. During treatment the frequency of both CD4+ and CD8+ T cells dropped and CD4+ T cells displayed an increased expression of programmed cell death-1 (PD-1). In vitro blocking of PD-1 successfully increased T-cell reactivity in all five samples isolated before radiotherapy but was less successful in restoring reactivity in samples isolated at later time points. Moreover, (chemo)radiotherapy was associated with an increase in both circulating monocytes and myeloid-derived suppressor cells (MDSCs) and an impaired capacity of APCs to stimulate allogeneic T cells. T-cell reactivity was slowly restored at 6–9 weeks after cessation of therapy. We conclude that conventional (chemo)radiotherapy profoundly suppresses the immune system in cervical cancer patients, and may restrict its combination with immunotherapy.

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Figure 1. Treatment and blood sampling schedule. Blood samples 1–5: blood samples for immunomonitoring. Numbers above the blood samples indicate the amount of patients who provided blood for immunomonitoring. Abbreviations: EBRT = external beam radiation therapy; ChTh = chemotherapy; BT = brachytherapy.
Figure 1. Treatment and blood sampling schedule. Blood samples 1–5: blood samples for immunomonitoring. Numbers above the blood samples indicate the amount of patients who provided blood for immunomonitoring. Abbreviations: EBRT = external beam radiation therapy; ChTh = chemotherapy; BT = brachytherapy.CC BY · PubMed Central
Figure 2. (Chemo)radiotherapy induced reduction in the absolute numbers of leukocytes and lymphocytes. (A) Time course of changes in the absolute number of leukocytes and lymphocytes before (baseline) treatment and during the first 5 d of fractionized radiotherapy. (B) Time course of changes in absolute number of leukocytes and lymphocytes before (baseline), during (15 fractions) and after (chemo)radiotherapy (3, 6 and 9 weeks after completion). Data are expressed as means ± SD, *p < 0.05. Abbreviations: fract = fractions; wks = weeks.
Figure 2. (Chemo)radiotherapy induced reduction in the absolute numbers of leukocytes and lymphocytes. (A) Time course of changes in the absolute number of leukocytes and lymphocytes before (baseline) treatment and during the first 5 d of fractionized radiotherapy. (B) Time course of changes in absolute number of leukocytes and lymphocytes before (baseline), during (15 fractions) and after (chemo)radiotherapy (3, 6 and 9 weeks after completion). Data are expressed as means ± SD, *p < 0.05. Abbreviations: fract = fractions; wks = weeks.CC BY · PubMed Central
Figure 3. The effect of (chemo)radiotherapy on T-cell reactivity. The response of circulating T cells against memory response mix (MRM; black bars) and influenza M1 protein-derived peptides (FLU; white bars) was measured in the lymphocyte stimulation test (LST). T cell proliferation is expressed as stimulation index + standard error of the mean (SEM) and shown at different time points, including baseline, after 15 fractions of EBRT and 3, 6 and 9 weeks after completion of EBRT. Data were analyzed by mixed model and expressed as means + SEM. *p <0.05 with respect to baseline. Abbreviations: wks = weeks; fract = fractions.
Figure 3. The effect of (chemo)radiotherapy on T-cell reactivity. The response of circulating T cells against memory response mix (MRM; black bars) and influenza M1 protein-derived peptides (FLU; white bars) was measured in the lymphocyte stimulation test (LST). T cell proliferation is expressed as stimulation index + standard error of the mean (SEM) and shown at different time points, including baseline, after 15 fractions of EBRT and 3, 6 and 9 weeks after completion of EBRT. Data were analyzed by mixed model and expressed as means + SEM. *p <0.05 with respect to baseline. Abbreviations: wks = weeks; fract = fractions.CC BY · PubMed Central
Figure 4. (Chemo)radiotherapy impairs the ability of antigen presenting cells to stimulate allogeneic T cells. Antigen presenting capacity of PBMCs as determined in a mixed lymphocyte reaction (MLR) in the blood samples from 10 patients are plotted over time. Treatment-induced changes in lymphocyte reactions as observed in the MLR based on (A) stimulation index (S.I.), expressed as mean ± SEM and (B) expressed as the fold changes (mean + SEM) of these S.I. over baseline. Time point include baseline, after 15 fractions of EBRT and at 3, 6 and 9 weeks after completion of EBRT. *p <0.05 with respect to baseline. Abbreviations: wks = weeks; fract = fractions.
Figure 4. (Chemo)radiotherapy impairs the ability of antigen presenting cells to stimulate allogeneic T cells. Antigen presenting capacity of PBMCs as determined in a mixed lymphocyte reaction (MLR) in the blood samples from 10 patients are plotted over time. Treatment-induced changes in lymphocyte reactions as observed in the MLR based on (A) stimulation index (S.I.), expressed as mean ± SEM and (B) expressed as the fold changes (mean + SEM) of these S.I. over baseline. Time point include baseline, after 15 fractions of EBRT and at 3, 6 and 9 weeks after completion of EBRT. *p <0.05 with respect to baseline. Abbreviations: wks = weeks; fract = fractions.CC BY · PubMed Central
Figure 5. (Chemo)radiotherapy alters the relative frequencies of circulating myeloid and lymphoid cells. (A) Percentages of lymphoid cells (CD3+CD19−) and myeloid cells (CD3−CD19−) of viable cells as measured by flow cytometry. Mean percentages are shown for 10 patients with a complete follow-up at different time points, including baseline, after 15 fractions of EBRT and at 3, 6 or 9 weeks after completion of EBRT. Percentage are expressed as mean ± SD. (B) Fold changes in lymphoid and myeloid cells over baseline. Fold changes are expressed as mean + SEM; *p <0.05 with respect to baseline. Abbreviations: wks = weeks; fract = fractions.
Figure 5. (Chemo)radiotherapy alters the relative frequencies of circulating myeloid and lymphoid cells. (A) Percentages of lymphoid cells (CD3+CD19−) and myeloid cells (CD3−CD19−) of viable cells as measured by flow cytometry. Mean percentages are shown for 10 patients with a complete follow-up at different time points, including baseline, after 15 fractions of EBRT and at 3, 6 or 9 weeks after completion of EBRT. Percentage are expressed as mean ± SD. (B) Fold changes in lymphoid and myeloid cells over baseline. Fold changes are expressed as mean + SEM; *p <0.05 with respect to baseline. Abbreviations: wks = weeks; fract = fractions.CC BY · PubMed Central
Figure 6. (Chemo)radiotherapy induces CD4+ T-cell suppression via PD-1. (A) Percentage of PD-1+ expressing CD4+ T cells for individual patients. (B) Aggregated fold changes of percentages with respect to baseline, *p <0.05 with respect to baseline. (C, D) Stimulation of five baseline PBMC samples with influenza Matrix 1 protein-derived peptides (FLU) in vitro in the presence (white bars) or absence (black bars) of PD-1 blocking using 1 μg/mL Nivolumab. (E, F) Stimulation of three post-treatment samples with FLU in vitro in the presence (white bars) or absence (black bars) of PD-1 blocking with 1 μg/mL Nivolumab. Displayed in (C) and (E) is the proliferation, expressed as counts per minute (cpm), shown as mean of triplicate wells plus standard deviation after stimulation. (D, F) Cytokine IFNγ production as measured within the supernatant of the proliferation assay, with and without PD-1 blocking. Abbreviations: wks = weeks; fract = fractions; cpm = counts per minute.
Figure 6. (Chemo)radiotherapy induces CD4+ T-cell suppression via PD-1. (A) Percentage of PD-1+ expressing CD4+ T cells for individual patients. (B) Aggregated fold changes of percentages with respect to baseline, *p <0.05 with respect to baseline. (C, D) Stimulation of five baseline PBMC samples with influenza Matrix 1 protein-derived peptides (FLU) in vitro in the presence (white bars) or absence (black bars) of PD-1 blocking using 1 μg/mL Nivolumab. (E, F) Stimulation of three post-treatment samples with FLU in vitro in the presence (white bars) or absence (black bars) of PD-1 blocking with 1 μg/mL Nivolumab. Displayed in (C) and (E) is the proliferation, expressed as counts per minute (cpm), shown as mean of triplicate wells plus standard deviation after stimulation. (D, F) Cytokine IFNγ production as measured within the supernatant of the proliferation assay, with and without PD-1 blocking. Abbreviations: wks = weeks; fract = fractions; cpm = counts per minute.CC BY · PubMed Central

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  1. Ganss R, 2002, Cancer Res, 62, 1462
  2. 10.1002/1097-0142(19951115)76 · DOI

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Authors
van Meir, H., Nout, R. A., Welters, M. J. P., Loof, N. M., de Kam, M. L., van Ham, J. J., Samuels, S., Kenter, G. G., Cohen, A. F., Melief, C. J. M., Burggraaf, J., van Poelgeest, M. I. E., & van der Burg, S. H.
Affiliations
  • Department of Gynecology, Leiden University Medical Center, Leiden, the Netherlands
  • Leiden University Medical Center (NL)
  • Centre for Human Drug Research, Leiden, the Netherlands
  • Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands
  • The Netherlands Cancer Institute (NL)
  • Centre for Human Drug Research (NL)
  • ISA Pharmaceuticals (Netherlands) (NL)
ORCID
Venue
OncoImmunology
Publisher
Informa UK Limited
Published
2017-02
Volume
6
Issue
2
Pages
e1267095
ISSN
  • 2162-4011 (ISSN-L)
  • 2162-402X
DOI
10.1080/2162402x.2016.1267095
PMC
PMC5353924
OpenAlex
W2567712538
Cited by
143
References
44
Citations by year
2026: 12 · 2025: 12 · 2024: 12 · 2023: 21 · 2022: 14 · 2021: 28 · 2020: 15 · 2019: 14 · 2018: 10 · 2017: 5
FWCI
5.21
Type
journal article
Language
en
Open access
Licence
Locations
  • OncoImmunology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
  • Leiden Repository (Leiden University) (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
Funders
Leids Universitair Medisch Centrum
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Health Sciences › Medicine › Obstetrics and Gynecology › Endometrial and Cervical Cancer Treatments
Keywords
cervical cancer, chemoradiotherapy, external beam radiotherapy, immunosuppression, T cell response, PD-1, myeloid-derived suppressor cells, antigen-presenting cells, CD4+ T cells, CD8+ T cells, monocytes, combination immunotherapy, immune monitoring

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