Combination Effect of Regulatory T-Cell Depletion and Ionizing Radiation in Mouse Models of Lung and Colon Cancer

Son, Cheol; Bae, Jae‐Ho; Shin, Dongjae; Lee, Hong-Rae; Jo, Wol-Soon; Yang, Kwangmo; Park, You-Soo

doi:10.1016/j.ijrobp.2015.01.011

Cited by 41 publications

(35 citation statements)

References 33 publications

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“…Systemic inhibition of Tregs using cycloheximide (CHX) and anti-CD25 antibodies proved to increase the number of CD8+ and CD4+ non-Tregs. Along with those results, CHX and anti-CD25-antibody treatment resulted in enhanced tumor regression, indicating a suppressive function of Tregs (63). In other in vivo studies, Tregs were suppressed by blockage of cytotoxic T-lymphocyte associated protein 4 (CTLA4) in mice injected with 4T1 mouse mammary carcinoma or CD-26 murine colon cancer cells.…”

Section: Action Of Immune Cells After Tumor Irradiationsupporting

confidence: 62%

“…On the other hand, immunosuppressive Tregs were found to be increased in irradiated tumors in an in vivo mouse study, bearing lung and colon tumors (63) as well as in tumors and tumor draining lymph nodes of mice injected with mouse melanoma and lymphoma cell lines (64). The increased presence of Tregs was associated with increased tumor growth and has been hypothesized to depend on Langerhans cells, the DCs in the epidermis (64).…”

Section: Action Of Immune Cells After Tumor Irradiationmentioning

confidence: 99%

“…The systemic inhibition of Tregs using CHX and anti-CD25-antibodies in an in vivo tumor-bearing mouse model (lung and colon carcinoma) or via CTLA4 blockage in an in vivo tumor-bearing mouse model (colon carcinoma) after irradiation of the tumor resulted in reduced growth of distant non-irradiated tumor cells (63, 74). The indicated suppressive action of Tregs on antitumor responses can thereby also be expected non-irradiated tumors.…”

Section: Action Of Immune Cells After Tumor Irradiationmentioning

confidence: 99%

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Intercellular Communication of Tumor Cells and Immune Cells after Exposure to Different Ionizing Radiation Qualities

Diegeler

Hellweg

2017

Front. Immunol.

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Ionizing radiation can affect the immune system in many ways. Depending on the situation, the whole body or parts of the body can be acutely or chronically exposed to different radiation qualities. In tumor radiotherapy, a fractionated exposure of the tumor (and surrounding tissues) is applied to kill the tumor cells. Currently, mostly photons, and also electrons, neutrons, protons, and heavier particles such as carbon ions, are used in radiotherapy. Tumor elimination can be supported by an effective immune response. In recent years, much progress has been achieved in the understanding of basic interactions between the irradiated tumor and the immune system. Here, direct and indirect effects of radiation on immune cells have to be considered. Lymphocytes for example are known to be highly radiosensitive. One important factor in indirect interactions is the radiation-induced bystander effect which can be initiated in unexposed cells by expression of cytokines of the irradiated cells and by direct exchange of molecules via gap junctions. In this review, we summarize the current knowledge about the indirect effects observed after exposure to different radiation qualities. The different immune cell populations important for the tumor immune response are natural killer cells, dendritic cells, and CD8+ cytotoxic T-cells. In vitro and in vivo studies have revealed the modulation of their functions due to ionizing radiation exposure of tumor cells. After radiation exposure, cytokines are produced by exposed tumor and immune cells and a modulated expression profile has also been observed in bystander immune cells. Release of damage-associated molecular patterns by irradiated tumor cells is another factor in immune activation. In conclusion, both immune-activating and -suppressing effects can occur. Enhancing or inhibiting these effects, respectively, could contribute to modified tumor cell killing after radiotherapy.

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Section: Action Of Immune Cells After Tumor Irradiationsupporting

confidence: 62%

Section: Action Of Immune Cells After Tumor Irradiationmentioning

confidence: 99%

Section: Action Of Immune Cells After Tumor Irradiationmentioning

confidence: 99%

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Intercellular Communication of Tumor Cells and Immune Cells after Exposure to Different Ionizing Radiation Qualities

Diegeler

Hellweg

2017

Front. Immunol.

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“…We and others have shown that Treg are upregulated in the tumor after a short course of radiation (18,38). In our experience, the use of CTLA-4 blockade was able to block the upregulation of Treg, thus enhancing the impact of radiation on the primary tumor and the abscopal effect at distant tumor sites (18).…”

Section: Discussionmentioning

confidence: 55%

In Situ Vaccination after Accelerated Hypofractionated Radiation and Surgery in a Mesothelioma Mouse Model

Maza

et al. 2017

Clinical Cancer Research

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How best to sequence and integrate immunotherapy into standard of care is currently unknown. Clinical protocols with accelerated nonablative hypofractionated radiation followed by surgery could provide an opportunity to implement immune checkpoint blockade. We therefore assessed the impact of nonablative hypofractionated radiation on the immune system in combination with surgery in a mouse mesothelioma model. Blunt surgery (R1 resection) was used to analyze the short-term effect, and radical surgery (R0 resection) was used to analyze the long-term effect of this radiation protocol before surgery. Nonablative hypofractionated radiation led to a specific immune activation against the tumor associated with significant upregulation of CD8 T cells, limiting the negative effect of an incomplete resection. The same radiation protocol performed 7 days before radical surgery led to a long-term antitumor immune protection that was primarily driven by CD4 T cells. Radical surgery alone or with a short course of nonablative radiation completed 24 hours before radical surgery did not provide this vaccination effect. Combining this radiation protocol with CTLA-4 blockade provided better results than radiation alone. The effect of PD-1 or PD-L1 blockade with this radiation protocol was less effective than the combination with CTLA-4 blockade. A specific activation of the immune system against the tumor contributes to the benefit of accelerated, hypofractionated radiation before surgery. Nonablative hypofractionated radiation combined with surgery provides an opportunity to introduce immune checkpoint blockades in the clinical setting. .

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“…This modification in turn results in increased trafficking and retention of T-cells within tumors (14,(30)(31)(32)(33). Meanwhile, several groups have demonstrated that radiation enhances Treg expansion and activation (34)(35)(36), indicating that targeting Tregs in radiation therapy may further enhance immunity. Indeed, Son et al combined radiation with Treg depletion using an antibody to CD25 and demonstrated that this enhanced radiation-mediated antitumor immunity, leading to prolonged overall survival.…”

Section: Il-2 Activates Cd8 + T-cells and A Subset Of Cd4 + T-cells Amentioning

confidence: 99%

Radiation Enhances the Efficacy of Antitumor Immunotherapy with an Immunocomplex of Interleukin-2 and its Monoclonal Antibody

Takahashi

Yasui

Minami

et al. 2017

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Combination Effect of Regulatory T-Cell Depletion and Ionizing Radiation in Mouse Models of Lung and Colon Cancer

Cited by 41 publications

References 33 publications

Intercellular Communication of Tumor Cells and Immune Cells after Exposure to Different Ionizing Radiation Qualities

Intercellular Communication of Tumor Cells and Immune Cells after Exposure to Different Ionizing Radiation Qualities

In Situ Vaccination after Accelerated Hypofractionated Radiation and Surgery in a Mesothelioma Mouse Model

Radiation Enhances the Efficacy of Antitumor Immunotherapy with an Immunocomplex of Interleukin-2 and its Monoclonal Antibody

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