Influence of low dose irradiation on differentiation, maturation and T-cell activation of human dendritic cells

Jahns, J; Anderegg, Ulf; Saalbach, Anja; Rosin, Britt; Patties, Ina; Glasow, Annegret; Kamprad, Manja; Scholz, Markus; Hildebrandt, Guido

doi:10.1016/j.mrfmmm.2011.02.007

Cited by 41 publications

(31 citation statements)

References 34 publications

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“…The effect of radiation on Ag presentation is expected to be dose dependent, with high doses being damaging. Our results partly correlate with a previous observation that radiation, in a single fraction of #2 Gy, does not affect Ag presentation (29), confirming that any positive effect of radiation on T cells is a direct effect. We used T cell lines as well as primary T cells purified from PBMC to study direct radiation effects.…”

Section: Discussionsupporting

confidence: 91%

Enhancement of T Cell Responses as a Result of Synergy between Lower Doses of Radiation and T Cell Stimulation

Spary

Al-Taei

Salimu

et al. 2014

The Journal of Immunology

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As a side effect of cancer radiotherapy, immune cells receive varying doses of radiation. Whereas high doses of radiation (>10 Gy) can lead to lymphopenia, lower radiation doses (2–4 Gy) represent a valid treatment option in some hematological cancers, triggering clinically relevant immunological changes. Based on our earlier observations, we hypothesized that lower radiation doses have a direct positive effect on T cells. In this study, we show that 0.6–2.4 Gy radiation enhances proliferation and IFN-γ production of PBMC or purified T cells induced by stimulation via the TCR. Radiation with 1.2 Gy also lowered T cell activation threshold and broadened the Th1 cytokine profile. Although radiation alone did not activate T cells, when followed by TCR stimulation, ERK1/2 and Akt phosphorylation increased above that induced by stimulation alone. These changes were followed by an early increase in glucose uptake. Naive (CD45RA+) or memory (CD45RA−) T cell responses to stimulation were boosted at similar rates by radiation. Whereas increased Ag-specific cytotoxic activity of a CD8+ T cell line manifested in a 4-h assay (10–20% increase), highly significant (5- to 10-fold) differences in cytokine production were detected in 6-d Ag-stimulation assays of PBMC, probably as a net outcome of death of nonstimulated and enhanced response of Ag-stimulated T cells. T cells from patients receiving pelvic radiation (2.2–2.75 Gy) also displayed increased cytokine production when stimulated in vitro. We report in this study enhanced T cell function induced by synergistic radiation treatment, with potential physiological significance in a wide range of T cell responses.

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Section: Discussionsupporting

confidence: 91%

Enhancement of T Cell Responses as a Result of Synergy between Lower Doses of Radiation and T Cell Stimulation

Spary

Al-Taei

Salimu

et al. 2014

The Journal of Immunology

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“…Immunologic cell death, when dying cells display immunologically favorable features, has indeed been suggested as a major mechanism of synergy between immunomodulation and irradiation (40). Because STxB-E7 directly targets DCs, another potential mechanism of interplay between irradiation and vaccination could be through the modulation of the function of DCs by ionizing radiation, as reported in in vitro settings (41). Experimental work is currently ongoing to elucidate these mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Synergy of Radiotherapy and a Cancer Vaccine for the Treatment of HPV-Associated Head and Neck Cancer

Mondini

Nizard

Tran

et al. 2015

Molecular Cancer Therapeutics

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There is growing interest in the association of radiotherapy and immunotherapy for the treatment of solid tumors. Here, we report an extremely effective combination of local irradiation (IR) and Shiga Toxin B (STxB)-based human papillomavirus (HPV) vaccination for the treatment of HPV-associated head and neck squamous cell carcinoma (HNSCC). The efficacy of the irradiation and vaccine association was tested using a model of HNSCC obtained by grafting TC-1/luciferase cells at a submucosal site of the inner lip of immunocompetent mice. Irradiation and the STxB-E7 vaccine acted synergistically with both single and fractionated irradiation schemes, resulting in complete tumor clearance in the majority of the treated mice. A dose threshold of 7.5 Gy was required to elicit the dramatic antitumor response. The combined treatment induced high levels of tumor-infiltrating, antigen-specific CD8 þ T cells, which were required to trigger the antitumor activity. Treatment with STxB-E7 and irradiation induced CD8 þ T-cell memory, which was sufficient to exert complete antitumor responses in both local recurrences and distant metastases. We also report for the first time that a combination therapy based on local irradiation and vaccination induces an increased pericyte coverage (as shown by aSMA and NG2 staining) and ICAM-1 expression on vessels. This was associated with enhanced intratumor vascular permeability that correlated with the antitumor response, suggesting that the combination therapy could also act through an increased accessibility for immune cells. The combination strategy proposed here offers a promising approach that could potentially be transferred into early-phase clinical trials.

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“…Immune cells are assumed to die at some natural rate μ I IðtÞ, which can also vary depending both on overall health of the patient and on various external stimuli, such as low-dose irradiation (Jahns et al, 2011). Finally, expansion of cytotoxic immune cells depends both proportionally to the number of tumor cells that have already been killed by the immune cells (de Pillis et al, 2005(de Pillis et al, , 2006, and proportionally to the amount of glucose available to the immune cells in tumor microenvironment.…”

Section: Model Descriptionmentioning

confidence: 99%

Cancer immunoediting: A process driven by metabolic competition as a predator–prey–shared resource type model

Kareva

Berezovskaya

2015

Journal of Theoretical Biology

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It is a well-established fact that tumors up-regulate glucose consumption to meet increasing demands for rapidly available energy by upregulating a purely glycolytic mode of glucose metabolism. What is often neglected is that activated cytotoxic cells of the immune system, integral players in the carcinogenesis process, also come to rely on glycolysis as a primary mode of glucose metabolism. Moreover, while cancer cells can revert back to aerobic metabolism, rapidly proliferating cytotoxic lymphocytes are incapable of performing their function when adequate resources are lacking. Consequently, it is likely that in the tumor microenvironment there may exist competition for shared resources between cancer cells and the cells of the immune system, which may underlie much of tumor-immune dynamics. Proposed here is a model of tumor-immune-glucose interactions, formulated as a predator-prey-common resource type system. The outcome of these interactions ranges from tumor elimination, to tumor dormancy, to unrestrained tumor growth. It is also predicted that the process of tumor escape can be preceded by periods of oscillatory tumor growth. A detailed bifurcation analysis of three subsystems of the model suggest that oscillatory regimes are a result of competition for shared resource (glucose) between the predator (immune cells) and the prey (cancer cells). Existence of competition for nutrients between cancer and immune cells may provide additional mechanistic insight as to why the efficacy of many immunotherapies may be limited.

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Influence of low dose irradiation on differentiation, maturation and T-cell activation of human dendritic cells

Cited by 41 publications

References 34 publications

Enhancement of T Cell Responses as a Result of Synergy between Lower Doses of Radiation and T Cell Stimulation

Enhancement of T Cell Responses as a Result of Synergy between Lower Doses of Radiation and T Cell Stimulation

Synergy of Radiotherapy and a Cancer Vaccine for the Treatment of HPV-Associated Head and Neck Cancer

Cancer immunoediting: A process driven by metabolic competition as a predator–prey–shared resource type model

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