In SituObservation of the Effects of Local Irradiation on Cytotoxic and Regulatory T Lymphocytes in Cervical Cancer Tissue

Abstract

Local radiotherapy is the major therapeutic approach to control inoperable cervical cancer. In this study, we analyzed the local immune microenvironment of cervical cancer before and after clinical radiation therapy to investigate whether tumor response due to immunomodulation. A total of 59 patients with pathologically diagnosed cervical cancers classified according to the International Federation of Obstetrics and Gynecology (FIGO) criteria were recruited. The patients were treated according to their disease status with standard radiation regimens. For each patient, tumor biopsies were conducted before, during and after radiation treatment with the doses of 0, 10, 20 and 30 Gy, respectively. All of the tumor samples were then grouped according to the doses delivered and tumor infiltrating lymphocytes with the biomarkers of CD8, CD4, FOXP3 and OX40 were measured by in situ immunohistochemistry. We found that before radiation treatment both CD8(+) T cell and CD4(+) T cell infiltrates were more present in the tumor stroma than in the tumor nests, while OX40(+) and FOXP3(+) T cell infiltrates were present at similar levels in both the tumor nests and stroma. After radiation treatment, the levels of CD8(+) T cells and CD4(+) T cells in the tumor nests and stroma were decreased compared with the levels before irradiation. However, OX40(+) T cells and FOXP3(+) T cells did not show any difference before and after irradiation, which indicates that the FOXP3(+) T cells were more resistant to ionizing radiation than were the cytotoxic effector T cells and demonstrates a dynamic rebalance of infiltrating lymphocytes in the tumor milieu occurs after radiotherapy. This suggest that local antitumor immunity could be compromised due to decreased cytotoxic effector cells and the relatively stable status of FOXP3(+) T cells after irradiation. Therefore, regulation of these FOXP3(+) T cells may be a potentially effective approach to enhance the efficacy of cancer radiation therapy.

Radiotherapy and the Tumor Stroma: The Importance of Dose and Fractionation

“…CD8 + T-cell recruitment and expansion in tumors is a good prognostic factor in many tumor types, whereas intratumoral Tregs are important promoters and stabilizers of immuno-suppressive conditions, therefore associated with poor prognosis (129). Preclinical studies on radiation-mediated effects on lymphocyte levels and profiles are somewhat contradictory, with some reports showing positive effects and others showing the opposite (130, 131). Most likely, the conflicting literature available underlines the fact that the immunological profile of cancers is tumor-type specific, and that local microenvironmental parameters such as degree of hypoxia, intratumoral pH, tumor stroma composition, and cytokine milieu are indeed key factors influencing local and systemic immune-responses after RT.…”

Tc17 Cells in Patients with Uterine Cervical Cancer

“…In our study, we also found a positive correlation between the frequency of Tc17 cell and microvessel density, supporting the proinflammatory property of IL-17–producing cells. Moreover, we also observed the correlation of Tc17 cells with Foxp3-expressing T cells in cervical cancer tissues,Foxp3-expressing T cells mediate strong immune-suppressive activity on T cell responses [39], [40]. These results indicate that Tc17 cells may promote tumor progression, but the exact function of Tc17 cells in UCC needs further investigation.…”

The importance of the tumor microenvironment in the therapeutic management of cancer

“…After irradiation, levels of CD4 + and CD8 + T cells decrease in the environment, while Treg cell levels remain unchanged [67]. The higher resistance of Treg cells to radiation would be due to the tumor necrosis factor receptor superfamily, member 4 (OX40) molecule [67].…”

“…After irradiation, levels of CD4 + and CD8 + T cells decrease in the environment, while Treg cell levels remain unchanged [67]. The higher resistance of Treg cells to radiation would be due to the tumor necrosis factor receptor superfamily, member 4 (OX40) molecule [67]. Further results in this direction indicate that overcoming the initial phase of immunosuppression could lead to a better immunogenic potential of radiotherapy [67].…”

“…The higher resistance of Treg cells to radiation would be due to the tumor necrosis factor receptor superfamily, member 4 (OX40) molecule [67]. Further results in this direction indicate that overcoming the initial phase of immunosuppression could lead to a better immunogenic potential of radiotherapy [67]. Besides, the presence of apoptotic cells may induce M2 macrophage polarization, which release immunosuppressive cytokines (IL-10 and TGF-b) [68].…”