• Adaptive immunity
• hematology
• innate immunity
• radiation combined burn injuries
• radio sensitivity

• Humans
• Burns/immunology
• Immunity, Innate
• Adaptive Immunity
• Animals
• Radiation Injuries/immunology
• Cytokines/metabolism

• Lactobacillus rhamnosus GG
• Th17/Treg
• cGAS/STING pathway
• gut microbiome
• intestinal immunity
• radiation induced intestinal injury

• Animals
• Lacticaseibacillus rhamnosus
• Gastrointestinal Microbiome/radiation effects
• Mice
• Probiotics/administration & dosage
• Mice, Inbred C57BL
• Radiation Injuries/immunology
• Macrophages/immunology
• Intestines/microbiology
• Intestines/radiation effects
• Intestines/immunology
• DNA Damage
• CD8-Positive T-Lymphocytes/immunology
• Membrane Proteins/metabolism
• T-Lymphocytes, Regulatory/immunology
• Male
• Th17 Cells/immunology
• Jejunum/radiation effects
• Jejunum/immunology
• Jejunum/microbiology
• Radiation-Protective Agents/pharmacology
• Radiation-Protective Agents/therapeutic use
• Radiation Injuries, Experimental/immunology
• Radiation Injuries, Experimental/prevention & control
• Nucleotidyltransferases

• cervical cancer
• raidotherapy
• risk score model
• tumor microenvironment
• tumor-infiltrating immune cells

• immune checkpoint inhibitors
• radiotherapy
• rectal cancer
• tumor microenvironment

• Radiotherapy
• cd4-CD8
• immune resistance
• pd-1/PD-L1
• t cell

• abscopal effect
• adrenergic signaling
• chronic stress
• immunosuppression
• radiation therapy

• P30 CA016056 NCI NIH HHS
• R01 CA099326 NCI NIH HHS
• P30CA016056 National Cancer Institute, Cairo University
• R01 CA236390 NCI NIH HHS
• R01 CA205246 NCI NIH HHS
• R01 CA236390, R01 CA099326, R01 CA205246 NIH HHS

• Bacterial dysbiosis
• Disease treatment
• Radiation enteritis
• Th17 cell

• cancer associated fibroblast
• immune microenvironment
• immunotherapy
• radiation therapy

• Cancer immunotherapy
• Radiation
• Regulatory T cells
• TREGS

In steady state, the intestinal epithelium forms an important part of the gut barrier to defend against luminal bacterial attack. However, the intestinal epithelium is compromised by ionizing irradiation due to its inherent self-renewing capacity. In this process, small intestinal bacterial overgrowth is a critical event that reciprocally alters the immune milieu. In other words, intestinal bacterial dysbiosis induces inflammation in response to intestinal injuries, thus influencing the repair process of irradiated lesions. In fact, it is accepted that commensal bacteria can generally enhance the host radiation sensitivity. To address the determination of radiation sensitivity, we hypothesize that Paneth cells press a critical “button” because these cells are central to intestinal health and disease by using their peptides, which are responsible for controlling stem cell development in the small intestine and luminal bacterial diversity. Herein, the most important question is whether Paneth cells alter their secretion profiles in the situation of ionizing irradiation. On this basis, the tolerance of Paneth cells to ionizing radiation and related mechanisms by which radiation affects Paneth cell survival and death will be discussed in this review. We hope that the relevant results will be helpful in developing new approaches against radiation enteropathy.

• Gut commensal bacteria
• Paneth cell
• Radiation enteropathy
• Epithelial homeostasis
• Gut immunity
• Intestinal defense

• Radiation-induced oxidative stress
• adaptive response
• molecular response

• Apoptosis
• N-acetylcysteine
• caspase-3
• ionizing radiation
• oxidative stress
• rat

• Acetylcysteine/pharmacology
• Animals
• Free Radical Scavengers/pharmacology
• Intestine, Small/drug effects
• Intestine, Small/radiation effects
• Male
• Oxidative Stress/drug effects
• Radiation Injuries/prevention & control
• Radiotherapy/adverse effects
• Rats
• Rats, Sprague-Dawley

The tumor microenvironment contributes to the survival and development of tumor cells and is therefore a key target for cancer therapy. The tumor microenvironment has unique physical and chemical properties and is associated with inflammation and immunity. To examine the correlation between tumor microenvironment-associated factors and the efficacy and prognosis of neoadjuvant therapy for rectal cancer, and to compare the differences between two treatments [neoadjuvant chemotherapy (NAC) vs. neoadjuvant chemoradiotherapy (NACR)], an immunohistochemical method was used to measure the expression levels of CD4⁺ tumor-infiltrating lymphocytes (TILs), cluster of differentiation (CD)8⁺TILs, forkhead box P3 (FOXP3)⁺TILs, cytotoxic T lymphocyte-associated antigen-4⁺TILs and programmed death ligand-1 (PD-L1)⁺TILs in 109 patients with rectal cancer, pre- and post-neoadjuvant therapy. The significance of these protein expression patterns was also analyzed using tissue microarrays, and the prognostic significance of these findings evaluated. The results indicated that high levels of CD4⁺TILs, CD8⁺TILs and PD-L1⁺TILs may be associated with favorable responses to neoadjuvant therapy, whereas high levels of FOXP3⁺TILs were associated with poor therapeutic responses. Expression levels of CD8⁺TILs and FOXP3⁺TILs following neoadjuvant therapy were independent prognostic factors and affected the total survival of patients subjected to neoadjuvant therapy for the treatment of rectal cancer. Moreover, the effects of NAC and NACR on the tumor microenvironment may be different.

• neoadjuvant therapy
• rectal cancer
• tissue microarrays
• tumor microenvironment
• tumor-infiltrating lymphocytes

Radiation is an important component of cancer treatment with more than half of all patients receive radiotherapy during their cancer experience. While the impact of radiation on tumour morphology is routinely examined in the pre-clinical and clinical setting, the impact of radiation on the tumour microenvironment and more specifically the inflammatory/immune response is less well characterised. Inflammation is a key contributor to short- and long-term cancer eradication, with significant tumour and normal tissue consequences. Therefore, the role of radiation in modulating the inflammatory response is highly topical given the current wave of targeted and immuno-therapeutic treatments for cancer. This review provides a general overview of how radiation modulates the inflammatory and immune response—(i) how radiation induces the inflammatory/immune system, (ii) the cellular changes that take place, (iii) how radiation dose delivery affects the immune response, and (iv) a discussion on research directions to improve patient survival, reduce side effects, improve quality of life, and reduce financial costs in the immediate future. Harnessing the benefits of radiation on the immune response will enhance its maximal therapeutic benefit and reduce radiation-induced toxicity.

• checkpoint inhibitors
• combination therapy
• immunotherapy
• prostate
• radiotherapy

• Bowel
• Mesenchymal stromal cells (MSCs)
• Radiotherapy side effects
• Regenerative medicine

• inflammation
• lymphocytes
• radiation
• tolerance
• tumor immunity

• R01 CA191234 NCI NIH HHS

• T cells
• abscopal effect
• fractionation
• immunotherapy
• inflammation
• radiotherapy

• Animals
• Antigens, Neoplasm/immunology
• Combined Modality Therapy
• Humans
• Immunotherapy/methods
• Neoplasm Metastasis/immunology
• Neoplasm Metastasis/radiotherapy
• Neoplasms/immunology
• Neoplasms/radiotherapy
• Radiotherapy Dosage

• MSC
• Th cells
• colon
• macrophage
• myofibroblast

• T lymphocytes
• adipose mesenchymal stromal cells
• bowel disease
• cellular therapy
• irradiation

Effective therapeutic strategies to address intestinal complications after radiation exposure are currently lacking. Mesenchymal stem cells (MSCs), which display the ability to repair the injured intestine, have been considered as delivery vehicles for repair genes. In this study, we evaluated the therapeutic effect of hepatocyte growth factor (HGF)-gene-modified MSCs on radiation-induced intestinal injury (RIII).

Female 6- to 8-week-old mice were radiated locally at the abdomen with a single 13-Gy dose of radiation and then treated with saline control, Ad-HGF or Ad-Null-modified MSCs therapy. The transient engraftment of human MSCs was detected via real-time PCR and immunostaining. The therapeutic effects of non- and HGF-modified MSCs were evaluated via FACS to determine the lymphocyte immunophenotypes; via ELISA to measure cytokine expression; via immunostaining to determine tight junction protein expression; via PCNA staining to examine intestinal epithelial cell proliferation; and via TUNEL staining to detect intestinal epithelial cell apoptosis.

The histopathological recovery of the radiation-injured intestine was significantly enhanced following non- or HGF-modified MSCs treatment. Importantly, the radiation-induced immunophenotypic disorders of the mesenteric lymph nodes and Peyer’s patches were attenuated in both MSCs-treated groups. Treatment with HGF-modified MSCs reduced the expression and secretion of inflammatory cytokines, including tumor necrosis factor alpha (TNF-α) and interferon-gamma (IFN-γ), increased the expression of the anti-inflammatory cytokine IL-10 and the tight junction protein ZO-1, and promoted the proliferation and reduced the apoptosis of intestinal epithelial cells.

Treatment of RIII with HGF-gene-modified MSCs reduces local inflammation and promotes the recovery of small intestinal histopathology in a mouse model. These findings might provide an effective therapeutic strategy for RIII.

• Animals
• Cytokines/blood
• Disease Models, Animal
• Female
• Genetic Therapy
• Hepatocyte Growth Factor/genetics
• Hepatocyte Growth Factor/therapeutic use
• Humans
• Immunity
• Immunophenotyping
• Inflammation Mediators/metabolism
• Intestines/immunology
• Intestines/injuries
• Lymph Nodes/pathology
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/cytology
• Mice, Inbred C57BL
• Peyer's Patches/pathology
• Radiation Injuries/blood
• Radiation Injuries/immunology
• Radiation Injuries/therapy
• Transduction, Genetic

• Immune therapy
• Radiotherapy
• Regulatory T cells
• Tumor

• Animals
• Humans
• Neoplasms/immunology
• Neoplasms/radiotherapy
• T-Lymphocytes, Regulatory/immunology
• T-Lymphocytes, Regulatory/radiation effects

• acute-phase inflammation
• high-protein diet
• radiation
• resveratrol

• Animals
• Anti-Inflammatory Agents, Non-Steroidal/pharmacology
• Anti-Inflammatory Agents, Non-Steroidal/therapeutic use
• Cytokines/blood
• Deoxyguanosine/urine
• Diet
• Dietary Proteins/administration & dosage
• Dietary Proteins/pharmacology
• Dietary Proteins/therapeutic use
• Dietary Supplements
• Female
• Immune System/cytology
• Immune System/drug effects
• Inflammation/blood
• Inflammation/etiology
• Inflammation/immunology
• Inflammation/therapy
• Leukocyte Count
• Lipid Metabolism
• Lipids/blood
• Neoplasms/radiotherapy
• Phytotherapy
• Plant Extracts/pharmacology
• Plant Extracts/therapeutic use
• Platelet Count
• Radiation Injuries, Experimental/blood
• Radiation Injuries, Experimental/immunology
• Radiation Injuries, Experimental/therapy
• Rats, Wistar
• Resveratrol
• Stilbenes/pharmacology
• Stilbenes/therapeutic use

• B16 melanoma
• Listeria monocytogenes-based vaccine
• anti-tumor immune response
• immunotherapy
• radiation therapy

• Antitumor effect
• dendritic cells
• electroporation-pulsed
• ionizing radiation
• irradiated tumor
• tumor cell lysate

• TLR ligands
• colon
• radiation

Erythema was observed on the skin of the first patients treated with radiation therapy. It is in particular to reduce this erythema, one feature of tissue inflammation, that prescribed dose to the tumor site started to be fractionated. It is now well known that radiation exposure of normal tissues generates a sustained and apparently uncontrolled inflammatory process. Radiation-induced inflammation is always observed, often described, sometimes partly explained, but still today far from being completely understood. The thing with the gut and especially the gut mucosa is that it is at the frontier between the external milieu and the organism, is in contact with a plethora of commensal and foreign antigens, possesses a dense-associated lymphoid tissue, and is particularly radiation sensitive because of a high mucosal turnover rate. All these characteristics make the gut mucosa a strong responsive organ in terms of radiation-induced immunoinflammation. This paper will focus on what has been observed in the normal gut and what remains to be done concerning the immunoinflammatory response following localized radiation exposure.

There is clinical interest in the modulation of regulatory T cells for cancer therapy. The safety of these therapies in combination with conventional anti-cancer therapies, including radiation therapy, can be studied in animal models. The effects of partial depletion of regulatory T (Treg) cells with an anti-CD25 antibody in conjunction with ionizing radiation on inflammation and tissue injury were analyzed in C57BL/6 mice. An anti-CD25 antibody (PC61) was administered 3 days prior to 13 Gy lower-half hemi-body irradiation (HBI). The blood, spleen, mesenteric lymph nodes (mLNs) and inguinal lymph nodes (iLNs) were harvested at various times thereafter. Alterations in the proportion of leukocyte subsets including CD4⁺ T cells, CD8⁺ T cells, Treg cells, B cells, NK cells, NK1.1⁺ T cells, macrophages and granulocytes were analyzed by FACS. The lungs, liver, pancreas, stomach, jejunum, duodenum, ileum, colon and kidney were harvested and studied by H&E staining. Expression of inflammatory mediators in plasma and tissue were investigated by ELISA. HBI significantly decreased the leukocyte pool though the various leukocyte subsets had different sensitivities to HBI. The administration of PC61 significantly decreased the proportion of Treg cells in spleen, iLN, mLN and blood (reduction of approximately 60%). Irradiation significantly increased the proportion of Treg cells in the spleen, iLN and mLN. HBI induced a systemic inflammatory reaction as demonstrated by increased plasma levels of IL-6, KC/CXCL1 and circulating granulocytes in the blood. Neutrophils also infiltrated the small bowel. The same general patterns were observed whether or not Treg cells were partially depleted with PC61 prior to HBI. These data demonstrate that partial depletion of Treg cells in these mice does not influence HBI-induced inflammatory response and tissue injury, and that combining anti-CD25 therapy with radiation may be safe and well tolerated in a clinical setting.

• t regulatory cells
• adoptive immunotherapy
• radiation therapy

• Animals
• B-Lymphocytes/radiation effects
• CD11c Antigen/metabolism
• Cell Proliferation/radiation effects
• Dendritic Cells/radiation effects
• Immunotherapy, Adoptive
• Interferon-gamma/biosynthesis
• Interleukin-2/administration & dosage
• Interleukin-2/therapeutic use
• Lymph Nodes/immunology
• Lymph Nodes/transplantation
• Melanoma/immunology
• Melanoma/radiotherapy
• Mice
• T-Lymphocytes, Regulatory/immunology
• T-Lymphocytes, Regulatory/metabolism
• T-Lymphocytes, Regulatory/radiation effects
• Tumor Microenvironment/radiation effects
• Tumor Necrosis Factor-alpha/biosynthesis

• R01 CA082529 NCI NIH HHS
• R56 CA082529 NCI NIH HHS
• T32 CA009672 NCI NIH HHS

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.

• T cells
• abscopal effect
• fractionation
• immunogenic cell death
• immunotherapy
• in situ vaccine
• inflammation
• radiation regimen

There is compelling evidence that lymphocytes are a recurring feature in radiation damaged normal tissues, but assessing their functional significance has proven difficult. Contradictory roles have been postulated in both tissue pathogenesis and protection, although these are not necessarily mutually exclusive as the immune system can display what may seem to be opposing faces at any one time. While the exact role of T lymphocytes in irradiated normal tissue responses may still be obscure, their accumulation after tissue damage suggests they may be critical targets for radiotherapeutic intervention and worthy of further study. This is accentuated by recent findings that pathologically damaged “self,” such as occurs after exposure to ionizing radiation, can generate danger signals with the ability to activate pathways similar to those that activate adoptive immunity to pathogens. In addition, the demonstration of T cell subsets with their recognition radars tuned to “self” moieties has revolutionized our ideas on how all immune responses are controlled and regulated. New concepts of autoimmunity have resulted based on the dissociation of immune functions between different subsets of immune cells. It is becoming axiomatic that the immune system has the power to regulate radiation-induced tissue damage, from failure of regeneration to fibrosis, to acute and chronic late effects, and even to carcinogenesis. Our understanding of the interplay between T lymphocytes and radiation-damaged tissue may still be rudimentary but this is a good time to re-examine their potential roles, their radiobiological and microenvironmental influences, and the possibilities for therapeutic manipulation. This review will discuss the yin and yang of T cell responses within the context of radiation exposures, how they might drive or protect against normal tissue side effects and what we may be able do about it.

• T cells
• Tregs
• radiation

• Tregs
• danger
• radiation