Abstract
BackgroundThe 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 TREG viability, phenotype, and suppressive activity.ResultsBoth natural and TGF-β1-induced CD4+ TREG cells exhibited increased resistance to radiation (10 Gy) as compared to CD4+ conventional T cells. Treatment, however, decreased Foxp3 expression in natural and induced TREG cells and the reduction was more robust in induced TREGS. Radiation also modulated the expression of signature iTREG molecules, inducing increased expression of LAG-3 and decreased expression of CD25 and CTLA-4. Despite the disconcordant modulation of suppressive molecules, irradiated iTREGS exhibited a reduced capacity to suppress the proliferation of CD8+ T cells.ConclusionsOur findings demonstrate that while human TREG cells are more resistant to radiation-induced death, treatment causes downregulation of Foxp3 expression, as well as modulation in the expression of TREG signature molecules associated with suppressive activity. Functionally, irradiated TGF-β1-induced TREGS 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 TREG activity, particularly when used in combination with cancer immunotherapies.
Highlights
The use of immunotherapy strategies for the treatment of advanced cancer is rapidly increasing
We evaluated the impact of radiation on the suppressive function of iTREGS and the expression of molecules associated with Regulatory T cell (TREG) functional activity: CD25, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), lymphocyte activation gene 3 (LAG-3), CD39, CD73, and programmed death ligand 1 (PD-L1)
We show that iTREG cell phenotype is directly modulated by radiation and that these cells are functionally less suppressive following radiotherapy. Both natural TREG and induced TREG cells are more resistant to cell death by radiation than CD4+ conventional T cells It has been reported that TREG cells preferentially survive radiation treatment compared to CD4+ conventional T (TCONV) cells in mice [36, 43, 44]
Summary
The use of immunotherapy strategies for the treatment of advanced cancer is rapidly increasing. 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. Efficient tumor control by immunotherapies relies on robust CD8+ cytotoxic T lymphocyte (CTL) activity [1,2,3] and these immune checkpoint blocking (ICB) antibodies release the inhibitory pathways restraining the action of CTLs. While the most effective immunotherapies in development seek to generate, promote, or stimulate tumorspecific CTLs, tumors often induce an immunosuppressive microenvironment that allows them to evade immune cell killing [4]. TREGS are capable of inhibiting the proliferation and killing activity of CTLs through several mechanisms including: [a] secretion of transforming growth factor-β1(TGF-β1) and IL10, [b] metabolic disruption through CD39 and CD73 [19], or [c] contact-dependent inhibition via cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), lymphocyte activation gene 3 (LAG-3), and programmed death ligand 1 (PD-L1) signaling [20, 21]
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