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A novel systemically administered Toll-like receptor 7 agonist potentiates the effect of ionizing radiation in murine solid tumor models.

Adlard AL, Dovedi SJ, Telfer BA, Koga-Yamakawa E, Pollard C, Honeychurch J, Illidge TM, Murata M, Robinson DT, Jewsbury PJ, Wilkinson RW, Stratford IJ - Int. J. Cancer (2014)

Bottom Line: Our data reveal that these long-term surviving mice have a significantly greater frequency of tumor antigen specific CD8(+) T cells when compared to age-matched tumor-naïve cells.To evaluate therapeutic effects on spontaneous metastases, we showed that combination of DSR-6434 with local IR of the primary tumor significantly reduced metastatic burden in the lung, when compared to time-matched cohorts treated with IR alone.Importantly, efficacy extends to sites outside of the field of irradiation, reducing metastatic load.

View Article: PubMed Central - PubMed

Affiliation: Experimental Oncology Group, School of Pharmacy and Pharmaceutical Sciences, Manchester Cancer Research Centre, University of Manchester, Manchester Academic Health Sciences Centre, United Kingdom.

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Combination therapy with IR and DSR-6434 elicits a tumor antigen-specific memory T-cell response in long-term surviving mice. (a)–(c) Splenocytes were isolated from tumor/treatment-naïve control mice (n = 3) and from long-term surviving (LTS) mice that had remained tumor free for greater than 90 days following DSR-6434/IR combination treatment (n = 5), and were co-cultured with 50-Gy-irradiated CT26 cells (a), AH1 peptide (b) or control peptide (c) for 6 days prior to restimulation with fresh 50-Gy-irradiated CT26 cells. The expression of IFNγ by CD8+ T cells was measured by flow cytometry. Representative plots of IFNγ expression by CD8+ T cells from LTS mice are shown to the right of each graph. ***p < 0.001, two-tailed Student's t-test.
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fig04: Combination therapy with IR and DSR-6434 elicits a tumor antigen-specific memory T-cell response in long-term surviving mice. (a)–(c) Splenocytes were isolated from tumor/treatment-naïve control mice (n = 3) and from long-term surviving (LTS) mice that had remained tumor free for greater than 90 days following DSR-6434/IR combination treatment (n = 5), and were co-cultured with 50-Gy-irradiated CT26 cells (a), AH1 peptide (b) or control peptide (c) for 6 days prior to restimulation with fresh 50-Gy-irradiated CT26 cells. The expression of IFNγ by CD8+ T cells was measured by flow cytometry. Representative plots of IFNγ expression by CD8+ T cells from LTS mice are shown to the right of each graph. ***p < 0.001, two-tailed Student's t-test.

Mentions: The capacity of CD8+ T cells isolated from LTS mice originally treated with IR and DSR-6434 to produce IFNγ following co-culture with irradiated CT26 cells was determined to evaluate whether immunological memory had been established. Our data revealed that splenocytes isolated from LTS mice had a significantly greater proportion of IFNγ-producing CD8+ T cells following co-culture with irradiated CT26 tumor cells when compared to age-matched tumor-naïve mice (18.1 ± 2 vs. 0.8 ± 0.1%; LTS and naïve mice, respectively) (Fig. 4a; p < 0.001). To determine whether this response was AH1 restricted, splenocytes were also cultured with either AH1 or a control peptide for 5 days followed by restimulation with irradiated CT26 cells for 16 hr. Following co-culture with AH1 peptide the frequency of IFNγ+ CD8+ T cells from splenocytes harvested from LTS mice originally treated with IR and DSR-6434 was significantly greater than that of naïve control mice (19.9 ± 3.7 vs. 1.3 ± 0.1 % respectively) (p < 0.001; Fig. 4b). In contrast, no significant differences in the frequency of IFNγ+ CD8+ T cells were found between splenocytes harvested from either LTS or naïve control mice following co-culture with irrelevant peptide (3.7 ± 1.1 vs. 1.1 ± 0.1%, respectively) (p > 0.05; Fig. 4c). Taken together, these data demonstrate that combination therapy involving IR and DSR-6434 generates long-term tumor antigen-specific immunological memory.


A novel systemically administered Toll-like receptor 7 agonist potentiates the effect of ionizing radiation in murine solid tumor models.

Adlard AL, Dovedi SJ, Telfer BA, Koga-Yamakawa E, Pollard C, Honeychurch J, Illidge TM, Murata M, Robinson DT, Jewsbury PJ, Wilkinson RW, Stratford IJ - Int. J. Cancer (2014)

Combination therapy with IR and DSR-6434 elicits a tumor antigen-specific memory T-cell response in long-term surviving mice. (a)–(c) Splenocytes were isolated from tumor/treatment-naïve control mice (n = 3) and from long-term surviving (LTS) mice that had remained tumor free for greater than 90 days following DSR-6434/IR combination treatment (n = 5), and were co-cultured with 50-Gy-irradiated CT26 cells (a), AH1 peptide (b) or control peptide (c) for 6 days prior to restimulation with fresh 50-Gy-irradiated CT26 cells. The expression of IFNγ by CD8+ T cells was measured by flow cytometry. Representative plots of IFNγ expression by CD8+ T cells from LTS mice are shown to the right of each graph. ***p < 0.001, two-tailed Student's t-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4286010&req=5

fig04: Combination therapy with IR and DSR-6434 elicits a tumor antigen-specific memory T-cell response in long-term surviving mice. (a)–(c) Splenocytes were isolated from tumor/treatment-naïve control mice (n = 3) and from long-term surviving (LTS) mice that had remained tumor free for greater than 90 days following DSR-6434/IR combination treatment (n = 5), and were co-cultured with 50-Gy-irradiated CT26 cells (a), AH1 peptide (b) or control peptide (c) for 6 days prior to restimulation with fresh 50-Gy-irradiated CT26 cells. The expression of IFNγ by CD8+ T cells was measured by flow cytometry. Representative plots of IFNγ expression by CD8+ T cells from LTS mice are shown to the right of each graph. ***p < 0.001, two-tailed Student's t-test.
Mentions: The capacity of CD8+ T cells isolated from LTS mice originally treated with IR and DSR-6434 to produce IFNγ following co-culture with irradiated CT26 cells was determined to evaluate whether immunological memory had been established. Our data revealed that splenocytes isolated from LTS mice had a significantly greater proportion of IFNγ-producing CD8+ T cells following co-culture with irradiated CT26 tumor cells when compared to age-matched tumor-naïve mice (18.1 ± 2 vs. 0.8 ± 0.1%; LTS and naïve mice, respectively) (Fig. 4a; p < 0.001). To determine whether this response was AH1 restricted, splenocytes were also cultured with either AH1 or a control peptide for 5 days followed by restimulation with irradiated CT26 cells for 16 hr. Following co-culture with AH1 peptide the frequency of IFNγ+ CD8+ T cells from splenocytes harvested from LTS mice originally treated with IR and DSR-6434 was significantly greater than that of naïve control mice (19.9 ± 3.7 vs. 1.3 ± 0.1 % respectively) (p < 0.001; Fig. 4b). In contrast, no significant differences in the frequency of IFNγ+ CD8+ T cells were found between splenocytes harvested from either LTS or naïve control mice following co-culture with irrelevant peptide (3.7 ± 1.1 vs. 1.1 ± 0.1%, respectively) (p > 0.05; Fig. 4c). Taken together, these data demonstrate that combination therapy involving IR and DSR-6434 generates long-term tumor antigen-specific immunological memory.

Bottom Line: Our data reveal that these long-term surviving mice have a significantly greater frequency of tumor antigen specific CD8(+) T cells when compared to age-matched tumor-naïve cells.To evaluate therapeutic effects on spontaneous metastases, we showed that combination of DSR-6434 with local IR of the primary tumor significantly reduced metastatic burden in the lung, when compared to time-matched cohorts treated with IR alone.Importantly, efficacy extends to sites outside of the field of irradiation, reducing metastatic load.

View Article: PubMed Central - PubMed

Affiliation: Experimental Oncology Group, School of Pharmacy and Pharmaceutical Sciences, Manchester Cancer Research Centre, University of Manchester, Manchester Academic Health Sciences Centre, United Kingdom.

Show MeSH
Related in: MedlinePlus