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 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.

Immune profile and immunosurveillance in treatment-naive and neoadjuvantly treated esophageal adenocarcinoma

“…Since the composition of the tumor microenvironment with immune cells and chemokines mainly drives efficacy of immunotherapy [24] and RCT profoundly suppresses the adaptive immune response, we propose that a combination of both could be restricted. Similar observations have been made in cervical and colorectal cancer patients [25,26].…”

“…Controversely, we could not observe any upregulation of PD-1 expression upon chemotherapy as described previously [25,26]. This might be due to the fact, that primary esophageal tumor samples show no differential expression of PD-1 and PD-L1 at all.…”

Impact of curative radiotherapy on the immune status of patients with localized prostate cancer

“…52 In contrast to these and our data, radio (chemo)therapy for cervical cancer induced a profound and long lasting (up to 9 weeks after treatment completion) decrease in CD4 + and CD8 + T cell subsets, but not in Tregs, hence does not seem promising for combination with immunotherapy. 53 Thus, it is important to test the effects of RT on the immune system in each clinical setting considered for combination of radio(chemo)therapy and immunotherapy. Notably, while peripheral changes are easy to monitor with routine blood sampling, they might not fully reflect the intratumoral situation, in which several immunological parameters have been described to predict outcome and therapy response.…”

Radiotherapy as a Backbone for Novel Concepts in Cancer Immunotherapy

“…Since some of these signals, including HMGB1, increase upon irradiation, radiation can increase MDSC abundance. In this line, a clinical study in cervical cancer patients was able to show elevated circulating MDSC levels upon irradiation [100]. On the other hand, mouse models suggest high doses of irradiation (30 Gy) to decrease MDSC abundance in the tumor [101].…”