Abdominal γ-Radiation Induces an Accumulation of Function-Impaired Regulatory T Cells in the Small Intestine

Billiard, Fabienne; Buard, Valérie; Benderitter, Marc; Linard, Christine

doi:10.1016/j.ijrobp.2010.12.041

Cited by 46 publications

(30 citation statements)

References 30 publications

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“…Reduced expression of various signaling molecules such as Foxp3 (recognized marker of Tregs), microenvironmental factors (CTLA-4), and anti-inflammatory cytokines (as IL-10) may contribute to impairment of Treg function. In our study, the reduced intestinal expression of IL-10, Foxp3 and CTLA-4 post-TBI suggest a defect of Tregs, which is inconsistent with results of studies with abdominal irradiation (40). Interestingly, BMT enhanced the recovery of IL-10 by day 14 post-TBI, suggesting that BMCs may play a role in maintaining mucosal homeostasis.…”

Section: Discussioncontrasting

confidence: 99%

Bone Marrow Transplantation Helps Restore the Intestinal Mucosal Barrier after Total Body Irradiation in Mice

et al. 2014

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Bone marrow transplantation (BMT) substantially improves 10-day survival after total body irradiation (TBI), consistent with an effect on intestinal radiation death. Total body irradiation, in addition to injuring the intestinal epithelium, also perturbs the mucosal immune system, the largest immune system in the body. This study focused on how transplanted bone marrow cells (BMCs) help restore mucosal immune cell populations after sublethal TBI (8.0 Gy). We further evaluated whether transplanted BMCs: (a) home to sites of radiation injury using green fluorescent protein labeled bone marrow; and (b) contribute to restoring the mucosal barrier in vivo. As expected, BMT accelerated recovery of peripheral blood (PB) cells. In the intestine, BMT was associated with significant early recovery of mucosal granulocytes (P = 0.005). Bone marrow transplantation did not affect mucosal macrophages or lymphocyte populations at early time points, but enhanced the recovery of these cells from day 14 onward (P = 0.03). Bone marrow transplantation also attenuated radiation-induced increase of intestinal CXCL1 and restored IL-10 levels (P = 0.001). Most importantly, BMT inhibited the post-radiation increase in intestinal permeability after 10 Gy TBI (P = 0.02) and modulated the expression of tight junction proteins (P = 0.01–0.05). Green fluorescent protein-positive leukocytes were observed both in intestinal tissue and in PB. These findings strongly suggest that BMT, in addition to enhancing general hematopoietic and immune system recovery, helps restore the intestinal immune system and enhances intestinal mucosal barrier function. These findings may be important in the development and understanding of strategies to alleviate or treat intestinal radiation toxicity.

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Section: Discussioncontrasting

confidence: 99%

Bone Marrow Transplantation Helps Restore the Intestinal Mucosal Barrier after Total Body Irradiation in Mice

et al. 2014

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“…Recent data indicate that Treg cells are intrinsically more radio resistant than other T cells and are proportionally increased after radiotherapy (91,92). Although it remains to be determined whether Treg suppressive activity is partially impaired after irradiation (92,93), an increase in Treg cells has been observed in some cancer patients undergoing radiotherapy (66,94).…”

Section: Why Are Abscopal Effects Uncommon?mentioning

confidence: 99%

Combining Radiotherapy and Cancer Immunotherapy: A Paradigm Shift

Formenti

Demaria²

2013

JNCI: Journal of the National Cancer Institute

878

703

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The therapeutic application of ionizing radiation has been largely based on its cytocidal power combined with the ability to selectively target tumors. Radiotherapy effects on survival of cancer patients are generally interpreted as the consequence of improved local control of the tumor, directly decreasing systemic spread. Experimental data from multiple cancer models have provided sufficient evidence to propose a paradigm shift, whereby some of the effects of ionizing radiation are recognized as contributing to systemic antitumor immunity. Recent examples of objective responses achieved by adding radiotherapy to immunotherapy in metastatic cancer patients support this view. Therefore, the traditional palliative role of radiotherapy in metastatic disease is evolving into that of a powerful adjuvant for immunotherapy. This combination strategy adds to the current anticancer arsenal and offers opportunities to harness the immune system to extend survival, even among metastatic and heavily pretreated cancer patients. We briefly summarize key evidence supporting the role of radiotherapy as an immune adjuvant. A critical appraisal of the current status of knowledge must include potential immunosuppressive effects of radiation that can hamper its capacity to convert the irradiated tumor into an in situ, individualized vaccine. Moreover, we discuss some of the current challenges to translate this knowledge to the clinic as more trials testing radiation with different immunotherapies are proposed.

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“…They identified a hypofractionated regimen with two fractions of 7.5 Gy as providing the best compromise between promotion of T cell cross-priming to tumor antigens versus relative induction of Treg (measured as increased Treg cell numbers) in the mouse B16 melanoma model. The mechanisms underlying Treg cells increase by radiation as well as their suppressive function in this setting remain to be clarified (Qu et al, 2010; Billiard et al, 2011; Kachikwu et al, 2011). …”

Section: Experiments Testing Dose Fractionationmentioning

confidence: 99%

Radiation as an immunological adjuvant: current evidence on dose and fractionation

Demaria¹,

Formenti²

2012

Front. Oncol.

268

230

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Ionizing radiation to a cancer site has the ability to convert the irradiated tumor in an immunogenic hub. However, radiation is a complex modifier of the tumor microenvironment and, by itself, is seldom sufficient to induce a therapeutically significant anti-tumor immune response, since it can also activate immune suppressive pathways. While several combinations of local radiation and immunotherapy have been shown in pre-clinical models to induce powerful anti-tumor immunity, the optimal strategy to achieve this effect remains to be defined. When used in vivo, radiation effects on tumors depend on the dose per fraction applied, the number of fractions used, and the total dose. Moreover, the interplay of these three variables is contingent upon the tumor setting studied, both in pre-clinical and clinical applications. To enable repair of the collateral damage to the normal tissue, radiation is usually given in multiple fractions, usually of 2 Gy. Generally, the use of larger fractions is limited to stereotactic applications, whereby optimal immobilization reduces inter- and intrafraction movement and permits a very conformal delivery of dose to the target, with optimal exclusion of normal tissue. Translation of the partnership of radiation and immunotherapy to the clinic requires a careful consideration of the radiation regimens used. To date, little is known on whether different dose/fractionation regimens have a specific impact on the anti-tumor immune response. Most experiments combining the two modalities were conducted with single fractions of radiotherapy. However, there is at least some evidencethat when combined with some specific immunotherapy approaches, the ability of radiation to promote anti-tumor immunity is dependent on the dose and fractionation employed. We critically review the available in vitro and in vivo data on this subject and discuss the potential impact of fractionation on the ability of radiation to synergize with immunotherapy.

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Abdominal γ-Radiation Induces an Accumulation of Function-Impaired Regulatory T Cells in the Small Intestine

Cited by 46 publications

References 30 publications

Bone Marrow Transplantation Helps Restore the Intestinal Mucosal Barrier after Total Body Irradiation in Mice

Bone Marrow Transplantation Helps Restore the Intestinal Mucosal Barrier after Total Body Irradiation in Mice

Combining Radiotherapy and Cancer Immunotherapy: A Paradigm Shift

Radiation as an immunological adjuvant: current evidence on dose and fractionation

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