Immunomodulatory Effects of Radiation: What is Next for Cancer Therapy?

Kumari, Anita; Simon, Samantha; Moody, Tomika; Garnett-Benson, Charlie

doi:10.2217/fon.15.300

Cited by 37 publications

(38 citation statements)

References 109 publications

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“…RT is a common treatment modality for cancer and is well documented to enhance antitumor immune responses by modulating tumor phenotypes, making them more susceptible to killing by CTLs [60]. The activity of CTLs, however, can be limited by suppressive T REGS .…”

Section: Discussionmentioning

confidence: 99%

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

2020

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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.

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Section: Discussionmentioning

confidence: 99%

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

2020

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“…TIC are of paramount importance when it comes to so-called immunomodulatory effects of cancer therapy. It has been shown that in addition to their cytotoxic effects chemotherapeutic and radiotherapeutic treatment has an immune-priming effect in the tumour microenvironment [ 1 , 2 ]. Antigen presenting cells initiate and shape the immune response, cytotoxic cells kill cancer cells and regulatory cells modulate the immune system and can impair the anti-tumoural immune response.…”

Section: Introductionmentioning

confidence: 99%

Spatial distribution of FoxP3+ and CD8+ tumour infiltrating T cells reflects their functional activity

et al. 2016

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BackgroundRegulatory and cytotoxic T cells are key players in the host's anticancer immune response. We studied the spatial distribution of FoxP+ and CD8+ cells to identify potential interactions.MethodsIn 202 patients 103 pre-radiochemotherapy biopsies and 153 post-radiochemotherapy tumour specimens of advanced rectal cancer were available and an immunohistochemical double staining of FoxP3+ and CD8+ tumour-infiltrating lymphocytes was performed to investigate cell density and cell-to-cell distances.ResultsFoxP3+ cells decreased after radiochemotherapy by a factor of 3 while CD8+ cells remained nearly unchanged. High epithelial (p=0.033) and stromal (p=0.009) FoxP3+ cell density was associated with an improved overall survival. Cell-to-cell distances of randomly distributed cells were simulated and compared to observed cell-to-cell distances. Observed distances shorter than the simulated, random distances were hypothesized to represent FoxP3+ cells actively interacting with CD8+ cells. Epithelial short distances were associated with a favourable prognosis while the opposite was true for the stromal compartment.ConclusionThe analysis of cell-to-cell distances may offer a tool to predict outcome, maybe by identifying functionally active, interacting infiltrating inflammatory cells in different tumour compartments.

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“…Therefore, Radiotherapy per se is an immunomodulatory and can be used as an adjuvant to immunotherapies. 28 On the other hand, immunotherapy wants to accelerate the immune system action against the tumor cells. It seems evident that the combination of radiotherapy and immunotherapy will provide good results in the fight against cancer.…”

Section: The Era Of Personalized Medicinementioning

confidence: 99%

Why should radiological oncology do translational research?

Cañas

Linares

Guedea

et al. 2019

Reports of Practical Oncology & Radiotherapy

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Radiological Oncology, like the rest of medical specialties, is beginning to provide can personalized therapies. The ongoing scientific advances enable a great degree of precision in diagnoses and therapies. To fight cancer, from a radiotherapy unit, requires up-to-date equipment, professionals with different specialties working in synchrony (doctors, physicists, biologists, etc.) and a lot of research. Some of the new therapeutic tendencies are immunotherapy, nanoparticles, gene therapy, biomarkers, artificial intelligence, etc. A new clinical paradigm in which new professional networks are inevitable is arising. The mission of translational research is to become a scientific engine in the clinical space.

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Immunomodulatory Effects of Radiation: What is Next for Cancer Therapy?

Cited by 37 publications

References 109 publications

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

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

Spatial distribution of FoxP3+ and CD8+ tumour infiltrating T cells reflects their functional activity

Why should radiological oncology do translational research?

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