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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 expression of the immune-related genes was evaluated by RT-PCR in tumor T1(A) and T2 (B); and the production of cytokine profile was determined by Luminex assay, where the concentrations are shown in pg/ml of culture medium (C).
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Figure 6: The expression of the immune-related genes was evaluated by RT-PCR in tumor T1(A) and T2 (B); and the production of cytokine profile was determined by Luminex assay, where the concentrations are shown in pg/ml of culture medium (C).

Mentions: RT-PCR results demonstrated that LRT combined with anti-CTLA-4 antibody resulted in upregulation of the immune-associated genes such as IFN-γ and its inducible protein perforin IP-10, cytolytic enzymes perforin and granzyme B, inducible costimulation molecule ICOS, DC maturation markers CD80 and CD86. This occurred in both T1 and T2 tumors compared with LRT alone or untreated tumors (Fig. 6A & 6B).


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 expression of the immune-related genes was evaluated by RT-PCR in tumor T1(A) and T2 (B); and the production of cytokine profile was determined by Luminex assay, where the concentrations are shown in pg/ml of culture medium (C).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: The expression of the immune-related genes was evaluated by RT-PCR in tumor T1(A) and T2 (B); and the production of cytokine profile was determined by Luminex assay, where the concentrations are shown in pg/ml of culture medium (C).
Mentions: RT-PCR results demonstrated that LRT combined with anti-CTLA-4 antibody resulted in upregulation of the immune-associated genes such as IFN-γ and its inducible protein perforin IP-10, cytolytic enzymes perforin and granzyme B, inducible costimulation molecule ICOS, DC maturation markers CD80 and CD86. This occurred in both T1 and T2 tumors compared with LRT alone or untreated tumors (Fig. 6A & 6B).

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