Limits...
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

T cells infiltrated into tumors T1 and T2 in both modelsA) Total T cells infiltrated into tumors were recognized by CD3-Alexa555 conjugated antibody (red), blood vascular endothelial cells were stained by CD31-Alexa488 (green), and all nuclei were stained by DAPI (blue), 400×. Representative images were acquired from T1 of each group in both models; B) Tumor-infiltrating T cells including total T cells and CD4+ and CD8+ T cells were quantified by flow cytometry. Tumor tissues were collected at 7 days after completion of treatment. Data shown were generated from T1 and T2 in the sequential model. The experiment was repeated twice.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4494951&req=5

Figure 3: T cells infiltrated into tumors T1 and T2 in both modelsA) Total T cells infiltrated into tumors were recognized by CD3-Alexa555 conjugated antibody (red), blood vascular endothelial cells were stained by CD31-Alexa488 (green), and all nuclei were stained by DAPI (blue), 400×. Representative images were acquired from T1 of each group in both models; B) Tumor-infiltrating T cells including total T cells and CD4+ and CD8+ T cells were quantified by flow cytometry. Tumor tissues were collected at 7 days after completion of treatment. Data shown were generated from T1 and T2 in the sequential model. The experiment was repeated twice.

Mentions: Fluorescent immunostaining demonstrated that more T cells infiltrated into the tumor T1 after local radiation combined with CTLA-4 blockade, whereas only a few T cells were observed to infiltrate into the untreated tumors (Fig. 3A).


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)

T cells infiltrated into tumors T1 and T2 in both modelsA) Total T cells infiltrated into tumors were recognized by CD3-Alexa555 conjugated antibody (red), blood vascular endothelial cells were stained by CD31-Alexa488 (green), and all nuclei were stained by DAPI (blue), 400×. Representative images were acquired from T1 of each group in both models; B) Tumor-infiltrating T cells including total T cells and CD4+ and CD8+ T cells were quantified by flow cytometry. Tumor tissues were collected at 7 days after completion of treatment. Data shown were generated from T1 and T2 in the sequential model. The experiment was repeated twice.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: T cells infiltrated into tumors T1 and T2 in both modelsA) Total T cells infiltrated into tumors were recognized by CD3-Alexa555 conjugated antibody (red), blood vascular endothelial cells were stained by CD31-Alexa488 (green), and all nuclei were stained by DAPI (blue), 400×. Representative images were acquired from T1 of each group in both models; B) Tumor-infiltrating T cells including total T cells and CD4+ and CD8+ T cells were quantified by flow cytometry. Tumor tissues were collected at 7 days after completion of treatment. Data shown were generated from T1 and T2 in the sequential model. The experiment was repeated twice.
Mentions: Fluorescent immunostaining demonstrated that more T cells infiltrated into the tumor T1 after local radiation combined with CTLA-4 blockade, whereas only a few T cells were observed to infiltrate into the untreated tumors (Fig. 3A).

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