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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

Total and activated CD4 and CD8 T cells from the splenocytes after overnight cultureA representative result from treatment with LRT versus LRT+Anti-CTLA4 compared with the untreated group was shown (A); Total CD4 and CD8 T cells had no significant difference (B), whereas the activated CD4 and CD8 T cells increased significantly in the group treated with LRT+Anti-CTLA4 compared with LRT alone (C). * represents comparison with untreated group and # represents comparison with LRT alone group, respectively. Comparison of in vitro cell killing of splenocytes derived from mice treated with LRT alone and LRT in combination with anti-CTLA4 mAb (D). A representative image shows the co-culture of splenocytes and target cells at a ratio of effector:target=20:1, resulting in tumor cell lysis after overnight culture in 2ml RPMI1640 complete medium in a 24-well plate. Blue: DAPI, Red: Actin, and Green: CD8 T cells.
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Figure 4: Total and activated CD4 and CD8 T cells from the splenocytes after overnight cultureA representative result from treatment with LRT versus LRT+Anti-CTLA4 compared with the untreated group was shown (A); Total CD4 and CD8 T cells had no significant difference (B), whereas the activated CD4 and CD8 T cells increased significantly in the group treated with LRT+Anti-CTLA4 compared with LRT alone (C). * represents comparison with untreated group and # represents comparison with LRT alone group, respectively. Comparison of in vitro cell killing of splenocytes derived from mice treated with LRT alone and LRT in combination with anti-CTLA4 mAb (D). A representative image shows the co-culture of splenocytes and target cells at a ratio of effector:target=20:1, resulting in tumor cell lysis after overnight culture in 2ml RPMI1640 complete medium in a 24-well plate. Blue: DAPI, Red: Actin, and Green: CD8 T cells.

Mentions: On day 20 after completion of radiation in the sequential setting (T1-T2), the splenocytes were cultured 5h to evaluate T cell activation. The percentages of total T cells and CD4/CD8 T cells in the spleen did not change dramatically in the group LRT versus LRT combined with CTLA-4 blockade, when compared with untreated group. However, the percentage of activated CD4 and CD8 T cells increased significantly in the combination group, especially activated CD8 T cells were almost three-fold higher than after LRT alone (Fig. 4A-C).


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)

Total and activated CD4 and CD8 T cells from the splenocytes after overnight cultureA representative result from treatment with LRT versus LRT+Anti-CTLA4 compared with the untreated group was shown (A); Total CD4 and CD8 T cells had no significant difference (B), whereas the activated CD4 and CD8 T cells increased significantly in the group treated with LRT+Anti-CTLA4 compared with LRT alone (C). * represents comparison with untreated group and # represents comparison with LRT alone group, respectively. Comparison of in vitro cell killing of splenocytes derived from mice treated with LRT alone and LRT in combination with anti-CTLA4 mAb (D). A representative image shows the co-culture of splenocytes and target cells at a ratio of effector:target=20:1, resulting in tumor cell lysis after overnight culture in 2ml RPMI1640 complete medium in a 24-well plate. Blue: DAPI, Red: Actin, and Green: CD8 T cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Total and activated CD4 and CD8 T cells from the splenocytes after overnight cultureA representative result from treatment with LRT versus LRT+Anti-CTLA4 compared with the untreated group was shown (A); Total CD4 and CD8 T cells had no significant difference (B), whereas the activated CD4 and CD8 T cells increased significantly in the group treated with LRT+Anti-CTLA4 compared with LRT alone (C). * represents comparison with untreated group and # represents comparison with LRT alone group, respectively. Comparison of in vitro cell killing of splenocytes derived from mice treated with LRT alone and LRT in combination with anti-CTLA4 mAb (D). A representative image shows the co-culture of splenocytes and target cells at a ratio of effector:target=20:1, resulting in tumor cell lysis after overnight culture in 2ml RPMI1640 complete medium in a 24-well plate. Blue: DAPI, Red: Actin, and Green: CD8 T cells.
Mentions: On day 20 after completion of radiation in the sequential setting (T1-T2), the splenocytes were cultured 5h to evaluate T cell activation. The percentages of total T cells and CD4/CD8 T cells in the spleen did not change dramatically in the group LRT versus LRT combined with CTLA-4 blockade, when compared with untreated group. However, the percentage of activated CD4 and CD8 T cells increased significantly in the combination group, especially activated CD8 T cells were almost three-fold higher than after LRT alone (Fig. 4A-C).

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