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Targeting the inhibitory receptor CTLA-4 on T cells increased abscopal effects in murine mesothelioma model.

Wu L, Wu MO, De la Maza L, Yun Z, Yu J, Zhao Y, Cho J, de Perrot M - Oncotarget (2015)

Bottom Line: We attempt to improve the local and abscopal effect by modulating T cell immunity with systemic blockade of CTLA-4 signal.The growth of primary tumors was significantly inhibited by LRT while CTLA-4 antibody enhanced the antitumor effect.LRT resulted in an increase of TIT, while CTLA-4 blockade led to significant reduction of Tregs and increase of cytotoxic T cells in both tumors.The abscopal effect is enhanced by targeting the immune checkpoints through modulation of T cell immune response in murine mesothelioma.

View Article: PubMed Central - PubMed

Affiliation: Latner Thoracic Surgery Research Laboratories and Division of Thoracic Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.

ABSTRACT
We previously demonstrated that blockade of immune suppressive CTLA-4 resulted in tumor growth delay when combined with chemotherapy in murine mesothelioma. Tumor-infiltrating T cells (TIT) after local radiotherapy (LRT) play critical roles in abscopal effect against cancer. We attempt to improve the local and abscopal effect by modulating T cell immunity with systemic blockade of CTLA-4 signal.The growth of primary tumors was significantly inhibited by LRT while CTLA-4 antibody enhanced the antitumor effect. Growth delay of the second tumors was achieved when the primary tumor was radiated. LRT resulted in more T cell infiltration into both tumors, including Treg and cytotoxic T cells. Interestingly, the proportion of Treg over effector T cells in both tumors was reversed after CTLA-4 blockade, while CD8 T cells were further activated. The expression of the immune-related genes was upregulated and cytokine production was significantly increased. LRT resulted in an increase of TIT, while CTLA-4 blockade led to significant reduction of Tregs and increase of cytotoxic T cells in both tumors. The abscopal effect is enhanced by targeting the immune checkpoints through modulation of T cell immune response in murine mesothelioma.

No MeSH data available.


Related in: MedlinePlus

The effect of T1 local radiation on the growth of T2 tumors in the absence or presence of systemic CTLA-4 blockadeA) The growth of primary and secondary tumors in sequential models. At day 10 after tumor cell injection of the primary site, the secondary tumor was challenged. LRT 5Gy was initiated on day 5 after tumor challenge onto the right thigh, and CTLA-4 blockade with its monoclonal antibody was given after completion of radiation (left diagram). The growth of primary (T1) and secondary tumor (T2) was shown in the middle and right panel, respectively. B) The growth of local and distant tumors in concurrent models. Two tumors T1 and T2 were challenged concurrently on day 0. Treatment schedule was shown in the diagram (bottom panel) and effect on tumor growth was shown in the top and middle panels. * represents comparison with untreated group and # represents comparison with LRT alone group, respectively.
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Figure 1: The effect of T1 local radiation on the growth of T2 tumors in the absence or presence of systemic CTLA-4 blockadeA) The growth of primary and secondary tumors in sequential models. At day 10 after tumor cell injection of the primary site, the secondary tumor was challenged. LRT 5Gy was initiated on day 5 after tumor challenge onto the right thigh, and CTLA-4 blockade with its monoclonal antibody was given after completion of radiation (left diagram). The growth of primary (T1) and secondary tumor (T2) was shown in the middle and right panel, respectively. B) The growth of local and distant tumors in concurrent models. Two tumors T1 and T2 were challenged concurrently on day 0. Treatment schedule was shown in the diagram (bottom panel) and effect on tumor growth was shown in the top and middle panels. * represents comparison with untreated group and # represents comparison with LRT alone group, respectively.

Mentions: The growth of primary tumors slowed down after local radiation, and the addition of CTLA-4 blockade improved the effect induced by radiation (Fig. 1A & 1B, middle panels). Interestingly, the secondary or distant tumors of mice whose primary tumor was treated with LRT grew slower than those of untreated mice. More strikingly, the Anti-CTLA4 following LRT gave rise to significant growth delay, and in the sequential model, some of the secondary tumors (3/9) were completely rejected (Fig. 1A & 1B, right panels), while treatment with Anti-CTLA4 alone had no effect on tumor growth.


Targeting the inhibitory receptor CTLA-4 on T cells increased abscopal effects in murine mesothelioma model.

Wu L, Wu MO, De la Maza L, Yun Z, Yu J, Zhao Y, Cho J, de Perrot M - Oncotarget (2015)

The effect of T1 local radiation on the growth of T2 tumors in the absence or presence of systemic CTLA-4 blockadeA) The growth of primary and secondary tumors in sequential models. At day 10 after tumor cell injection of the primary site, the secondary tumor was challenged. LRT 5Gy was initiated on day 5 after tumor challenge onto the right thigh, and CTLA-4 blockade with its monoclonal antibody was given after completion of radiation (left diagram). The growth of primary (T1) and secondary tumor (T2) was shown in the middle and right panel, respectively. B) The growth of local and distant tumors in concurrent models. Two tumors T1 and T2 were challenged concurrently on day 0. Treatment schedule was shown in the diagram (bottom panel) and effect on tumor growth was shown in the top and middle panels. * represents comparison with untreated group and # represents comparison with LRT alone group, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494951&req=5

Figure 1: The effect of T1 local radiation on the growth of T2 tumors in the absence or presence of systemic CTLA-4 blockadeA) The growth of primary and secondary tumors in sequential models. At day 10 after tumor cell injection of the primary site, the secondary tumor was challenged. LRT 5Gy was initiated on day 5 after tumor challenge onto the right thigh, and CTLA-4 blockade with its monoclonal antibody was given after completion of radiation (left diagram). The growth of primary (T1) and secondary tumor (T2) was shown in the middle and right panel, respectively. B) The growth of local and distant tumors in concurrent models. Two tumors T1 and T2 were challenged concurrently on day 0. Treatment schedule was shown in the diagram (bottom panel) and effect on tumor growth was shown in the top and middle panels. * represents comparison with untreated group and # represents comparison with LRT alone group, respectively.
Mentions: The growth of primary tumors slowed down after local radiation, and the addition of CTLA-4 blockade improved the effect induced by radiation (Fig. 1A & 1B, middle panels). Interestingly, the secondary or distant tumors of mice whose primary tumor was treated with LRT grew slower than those of untreated mice. More strikingly, the Anti-CTLA4 following LRT gave rise to significant growth delay, and in the sequential model, some of the secondary tumors (3/9) were completely rejected (Fig. 1A & 1B, right panels), while treatment with Anti-CTLA4 alone had no effect on tumor growth.

Bottom Line: We attempt to improve the local and abscopal effect by modulating T cell immunity with systemic blockade of CTLA-4 signal.The growth of primary tumors was significantly inhibited by LRT while CTLA-4 antibody enhanced the antitumor effect.LRT resulted in an increase of TIT, while CTLA-4 blockade led to significant reduction of Tregs and increase of cytotoxic T cells in both tumors.The abscopal effect is enhanced by targeting the immune checkpoints through modulation of T cell immune response in murine mesothelioma.

View Article: PubMed Central - PubMed

Affiliation: Latner Thoracic Surgery Research Laboratories and Division of Thoracic Surgery, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.

ABSTRACT
We previously demonstrated that blockade of immune suppressive CTLA-4 resulted in tumor growth delay when combined with chemotherapy in murine mesothelioma. Tumor-infiltrating T cells (TIT) after local radiotherapy (LRT) play critical roles in abscopal effect against cancer. We attempt to improve the local and abscopal effect by modulating T cell immunity with systemic blockade of CTLA-4 signal.The growth of primary tumors was significantly inhibited by LRT while CTLA-4 antibody enhanced the antitumor effect. Growth delay of the second tumors was achieved when the primary tumor was radiated. LRT resulted in more T cell infiltration into both tumors, including Treg and cytotoxic T cells. Interestingly, the proportion of Treg over effector T cells in both tumors was reversed after CTLA-4 blockade, while CD8 T cells were further activated. The expression of the immune-related genes was upregulated and cytokine production was significantly increased. LRT resulted in an increase of TIT, while CTLA-4 blockade led to significant reduction of Tregs and increase of cytotoxic T cells in both tumors. The abscopal effect is enhanced by targeting the immune checkpoints through modulation of T cell immune response in murine mesothelioma.

No MeSH data available.


Related in: MedlinePlus