Ionizing radiation modulates the phenotype and function of human CD4+ induced regulatory T cells

Abstract

Background: The use of immunotherapy strategies for the treatment of advanced cancer is rapidly increasing. Most immunotherapies rely on induction of CD8+ tumor-specific cytotoxic T cells that are capable of directly killing cancer cells. Tumors, however, utilize a variety of mechanisms that can suppress anti-tumor immunity. CD4+ regulatory T cells can directly inhibit cytotoxic T cell activity and these cells can be recruited, or induced, by cancer cells allowing escape from immune attack. The use of ionizing radiation as a treatment for cancer has been shown to enhance anti-tumor immunity by several mechanisms including immunogenic tumor cell death and phenotypic modulation of tumor cells. Less is known about the impact of radiation directly on suppressive regulatory T cells. In this study we investigate the direct effect of radiation on human T REG viability, phenotype, and suppressive activity. Results: Both natural and TGF-β1-induced CD4+ T REG cells exhibited increased resistance to radiation (10 Gy) as compared to CD4+ conventional T cells. Treatment, however, decreased Foxp3 expression in natural and induced T REG cells and the reduction was more robust in induced T REGS. Radiation also modulated the expression of signature iT REG molecules, inducing increased expression of LAG-3 and decreased expression of CD25 and CTLA-4. Despite the disconcordant modulation of suppressive molecules, irradiated iT REGS exhibited a reduced capacity to suppress the proliferation of CD8+ T cells. Conclusions: Our findings demonstrate that while human T REG cells are more resistant to radiation-induced death, treatment causes downregulation of Foxp3 expression, as well as modulation in the expression of T REG signature molecules associated with suppressive activity. Functionally, irradiated TGF-β1-induced T REGS were less effective at inhibiting CD8+ T cell proliferation. These data suggest that doses of radiotherapy in the hypofractionated range could be utilized to effectively target and reduce T REG activity, particularly when used in combination with cancer immunotherapies.

RETRACTED ARTICLE: Gamma-radiated immunosuppressed tumor xenograft mice can be a new ideal model in cancer research

“…Similar to our results, Kajioka et al (1999) have evaluated the responses of CD19 + B cells, CD4 + , and CD8 + lymphocytes against the whole-body radiation on the 3 Gry gamma-radiated mice. Their observations showed significantly less change in the rate of CD19 + B cells and CD4 + and CD8 + lymphocytes in the gamma-radiated mice 28 . Likewise, a more radiosensitive from CD19 + B cells was observed compared to CD4 + and CD8 + lymphocytes 29 .…”

Persistent anti-NY-ESO-1-specific T cells and expression of differential biomarkers in a patient with metastatic gastric cancer benefiting from combined radioimmunotherapy treatment: a case report

“…20 Similarly, it has been demonstrated that irradiated Tregs can exhibit a reduced capacity to suppress the proliferation of CD8 + T cells particularly when combined radioimmunotherapies are used. 21 In the present report, Tregs distribution was low and comparable at disease resolution and disease re-progression in the peripheral blood of the patient. In line with our result, it has been demonstrated recently that Tregs with suppressive activity were upregulated on tumor-infiltrating T cells from patients with gastric cancer compared with their expressions on corresponding peripheral blood.…”

“…20 Similarly, it has been demonstrated that irradiated Tregs can exhibit a reduced capacity to suppress the proliferation of CD8 + T cells particularly when combined radioimmunotherapies are used. 21 To this end, we analyzed the presence of the Tregs (CD4 ++ CD25 high FOXP3 + ) population at disease resolution and disease re-progression in the peripheral blood mononuclear cells of the patient. Tregs distribution was low and comparable at both disease stages (online supplementary figure S3).…”

Gamma-ray irradiation modulates PGRMC1 expression and the number of CD56+ and FoxP3+ cells in the tumor microenvironment of endometrial endometrioid adenocarcinoma

“…For instance, they may suppress the effector immune response and help the tumor grow, whilst downregulating inflammation and thereby protecting the host from tumor progression [28]. Beauford et al [29] revealed that human Tregs from healthy donors are more resistant to radiation-induced death than other immune cells. An increase in FoxP3 cell numbers in the TME is possibly induced by two mechanisms; post-radiation transforming growth factor-β1 (TGF-β1) secretion by cells in the cancer stroma and radioresistance of tumor-infiltrated Tregs.…”