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

Our plain-English summary of Targeting the inhibitory receptor CTLA-4 on T cells increased abscopal effects in murine mesothelioma model, by L. Wu, M.O. Wu, L. De la Maza, et al (Oncotarget, 2015).

The study

• Authors: L. Wu, M.O. Wu, L. De la Maza, Z. Yun, J. Yu, Y. Zhao, J. Cho, M. de Perrot
• Journal: Oncotarget
• Published: 2015;6(14):12468-80
• Cited by: 63 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This was a laboratory study in mice and cultured cells. It did not study asbestos exposure. The authors injected a mouse mesothelioma cell line (AB12) under the skin of female Balb/c mice, in the right hind leg (first tumor) and the right flank (second tumor), either on the same day or 10 days apart. Only the leg tumor received radiation, 5 Gy daily for 3 days. Some mice then received two injections of an antibody that blocks CTLA-4, a molecule that holds back immune T cells. Radiation slowed the growth of the irradiated tumor and of the distant, non-irradiated tumor, and adding the antibody increased this effect. In mice given radiation followed by the antibody in the 10-days-apart model, 3 of 9 second tumors were completely rejected. The antibody alone had no effect on tumor growth. In immune-deficient mice, distant tumor growth did not differ significantly with radiation. Radiation raised the proportion of regulatory T cells in both tumors, and the antibody reversed this. The authors concluded that CTLA-4 blockade enhanced radiation's effect on distant tumors in murine mesothelioma.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment in mice, with supporting experiments on cultured mouse mesothelioma cells
• Who was studied: 6-8 week-old female Balb/c mice given subcutaneous tumors of the AB12 mouse mesothelioma cell line (2 million cells) in the right hind leg and right flank. Immune-deficient NOD/SCID mice served as controls. The text does not give total numbers of mice per group.
• Exposure: No asbestos exposure was studied. Treatments were local gamma-ray radiation of the leg tumor (5 Gy once daily on days 5, 6 and 7), followed in some groups by anti-mouse CTLA-4 monoclonal antibody, 100 µg per mouse injected into the abdomen twice (days 8 and 9).
• Main results:
  • In cultured AB12 cells, about 10% survived a 5 Gy dose. Cells given 10 Gy or more could no longer form colonies.
  • In Balb/c mice, growth of the irradiated (primary) tumor slowed after radiation, and adding CTLA-4 blockade improved the effect.
  • Second (distant, non-irradiated) tumors grew more slowly in mice whose primary tumor was irradiated than in untreated mice.
  • In mice given radiation followed by anti-CTLA-4, distant tumors showed significant growth delay, and in the sequential model 3 of 9 second tumors were completely rejected. Anti-CTLA-4 alone had no effect on tumor growth.
  • In immune-deficient NOD/SCID mice, distant tumor growth was not significantly different between radiation-treated and untreated groups.
  • In a separate experiment, injecting irradiated tumor cells slowed growth of tumors on the opposite flank, but the effect was transient and did not last beyond 11 days.
  • In the spleen, activated CD8 T cells were almost three-fold higher with radiation plus CTLA-4 blockade than with radiation alone.
  • Radiation increased regulatory T cells and the ratio of regulatory T cells to effector CD8 T cells in both tumors on day 7, and CTLA-4 blockade reversed this.
  • Several cytokines (including IFN-γ, IL-6 and IL-17A) in cultured spleen cells were higher with radiation plus CTLA-4 blockade than with radiation alone.
• The authors' conclusion: The authors concluded that radiation of the primary tumor had an effect on the distant tumor, and that this effect was enhanced by systemic CTLA-4 blockade through changes in the T cell immune response in murine mesothelioma.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: CTLA-4, Mesothelioma, Chemotherapy, Cytokine.

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