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

H van Meir, R A Nout, M J P Welters, N M Loof, M L de Kam, J J van Ham, S Samuels, G G Kenter, A F Cohen, C J M Melief, J Burggraaf, M I E van Poelgeest, S H van der Burg

Research output: Contribution to journalArticleAcademicpeer-review

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 vitroblocking 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.

Original languageEnglish
Pages (from-to)e1267095
JournalOncoImmunology
Volume6
Issue number2
DOIs
Publication statusPublished - 2017

Cite this

van Meir, H., Nout, R. A., Welters, M. J. P., Loof, N. M., de Kam, M. L., van Ham, J. J., ... van der Burg, S. H. (2017). Impact of (chemo)radiotherapy on immune cell composition and function in cervical cancer patients. OncoImmunology, 6(2), e1267095. https://doi.org/10.1080/2162402X.2016.1267095
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. / Impact of (chemo)radiotherapy on immune cell composition and function in cervical cancer patients. In: OncoImmunology. 2017 ; Vol. 6, No. 2. pp. e1267095.
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van Meir, H, Nout, RA, Welters, MJP, Loof, NM, de Kam, ML, van Ham, JJ, Samuels, S, Kenter, GG, Cohen, AF, Melief, CJM, Burggraaf, J, van Poelgeest, MIE & van der Burg, SH 2017, 'Impact of (chemo)radiotherapy on immune cell composition and function in cervical cancer patients' OncoImmunology, vol. 6, no. 2, pp. e1267095. https://doi.org/10.1080/2162402X.2016.1267095

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

In: OncoImmunology, Vol. 6, No. 2, 2017, p. e1267095.

Research output: Contribution to journalArticleAcademicpeer-review

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AU - van Meir, H

AU - Nout, R A

AU - Welters, M J P

AU - Loof, N M

AU - de Kam, M L

AU - van Ham, J J

AU - Samuels, S

AU - Kenter, G G

AU - Cohen, A F

AU - Melief, C J M

AU - Burggraaf, J

AU - van Poelgeest, M I E

AU - van der Burg, S H

PY - 2017

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N2 - 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 vitroblocking 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.

AB - 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 vitroblocking 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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