title: Impact of (chemo)radiotherapy on immune cell composition and function in cervical cancer patients.
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.
authors.affiliation: Department of Gynecology, Leiden University Medical Center, Leiden, the Netherlands; Centre for Human Drug Research, Leiden, the Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: van Meir
authors.affiliation: Department of Radiation Oncology, Leiden University Medical Center , Leiden, the Netherlands.
authors.forename: R A
authors.initials: RA
authors.lastname: Nout
authors.affiliation: Department of Medical Oncology, Leiden University Medical Center , Leiden, the Netherlands.
authors.forename: M J P
authors.initials: MJ
authors.lastname: Welters
authors.affiliation: Department of Medical Oncology, Leiden University Medical Center , Leiden, the Netherlands.
authors.forename: N M
authors.initials: NM
authors.lastname: Loof
authors.affiliation: Centre for Human Drug Research , Leiden, the Netherlands.
authors.forename: M L
authors.initials: ML
authors.lastname: de Kam
authors.affiliation: Department of Medical Oncology, Leiden University Medical Center , Leiden, the Netherlands.
authors.forename: J J
authors.initials: JJ
authors.lastname: van Ham
authors.affiliation: Center Gynecological Oncology Amsterdam , NKI-AvL , Amsterdam, the Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Samuels
authors.affiliation: Center Gynecological Oncology Amsterdam , NKI-AvL , Amsterdam, the Netherlands.
authors.forename: G G
authors.initials: GG
authors.lastname: Kenter
authors.affiliation: Centre for Human Drug Research , Leiden, the Netherlands.
authors.forename: A F
authors.initials: AF
authors.lastname: Cohen
authors.affiliation: ISA Pharmaceuticals , Leiden, the Netherlands.
authors.forename: C J M
authors.initials: CJ
authors.lastname: Melief
authors.affiliation: Centre for Human Drug Research , Leiden, the Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Burggraaf
authors.affiliation: Department of Gynecology, Leiden University Medical Center , Leiden, the Netherlands.
authors.forename: M I E
authors.initials: MI
authors.lastname: van Poelgeest
authors.affiliation: Department of Medical Oncology, Leiden University Medical Center , Leiden, the Netherlands.
authors.forename: S H
authors.initials: SH
authors.lastname: van der Burg
keywords: Cervical cancer; PD-1; immunomonitoring; immunosuppression; radiotherapy