Local effector failure in mesothelioma is not mediated by CD4+ CD25+ T-regulator cells

Our plain-English summary of Local effector failure in mesothelioma is not mediated by CD4+ CD25+ T-regulator cells, by C. Jackaman, S. Cornwall, A.M. Lew, et al (The European Respiratory Journal, 2009).

The study

• Authors: C. Jackaman, S. Cornwall, A.M. Lew, Y. Zhan, B.W. Robinson, D.J. Nelson
• Journal: The European Respiratory Journal
• Published: 2009;34(1):162-75
• Cited by: 22 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

The aim of the present study was to define the point at which mesothelioma T-cell responses fail in order to design better immunotherapies. A murine model of mesothelioma was used which was established with asbestos. Inoculation of tumour cells into syngeneic mice results in progressing tumours with similar histopathology to human mesothelioma. The tumour cells secrete a marker tumour antigen similar to secreted tumour-associated products, such as mesothelin. The mesothelioma microenvironment contains stromal elements including dendritic cells, effector CD8(+) and CD4(+) T-cells, and CD4(+) T-regulatory (Tregs) cells, all of which are activated in situ, implying chronic inflammation. Tumour antigens are rapidly transported to draining lymph nodes wherein tumour-specific T-cell responses are generated. Despite the generation of potent CD8(+) cytotoxic lymphocyte in lymphoid organs, those that infiltrate tumours cannot restrain tumour growth suggesting local suppression. Splenic Tregs did not suppress protective responses in adoptive transfer experiments suggesting that systemic Tregs play little role in regulating anti-mesothelioma immune responses. Finally, removal of CD25(+) Tregs from the tumour site and lymphoid organs did not alter tumour growth with or without interleukin (IL)-2 or IL-21 immunotherapy. Tregs are not potent regulators of anti-mesothelioma immunity and targeting these cells may not improve results.

In plain English

This was a laboratory study in mice, not people. The authors used a mouse mesothelioma cell line, AE17, originally made by injecting asbestos fibres into the peritoneal (abdominal) cavity of mice. They also used a version engineered to secrete a marker protein, ovalbumin, so that immune responses to the tumour could be tracked. Tumour cells were injected under the skin. Tumour antigen reached the draining lymph nodes early, and tumour-specific killer (CD8+) T-cells formed there and then spread through the body. CD8+ cells made up only 3.4–5.2% of the cells in the tumour samples. These cells appeared activated but showed no sign of killing target cells within the tumour. Spleen cells from tumour-bearing mice protected healthy mice that were later given tumour cells. In mice with established tumours, removing CD25+ cells, which include regulatory T-cells (Tregs), with an antibody did not change tumour growth. It did not help interleukin-21 treatment and it removed the effect of interleukin-2 treatment. The authors concluded that Tregs are not potent regulators of anti-mesothelioma immunity and that targeting them may not improve results.

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 (mouse model of mesothelioma)
• Who was studied: Female C57Bl/6J mice aged 6–8 weeks, plus genetically modified mouse lines (OT-1, GK mice lacking peripheral CD4 T-cells, perforin-deficient mice), housed in Perth and Melbourne, Australia. Experimental groups were generally 5 to 12 mice.
• Exposure: Mice were not exposed to asbestos in this study. They were injected under the skin of the flank with AE17 mesothelioma cells, a cell line originally derived from mice injected with asbestos fibres (fibre type not named), or with an ovalbumin-secreting version (AE17-sOVA). Some mice were also given antibody depletion of CD4+, CD8+ or CD25+ cells, interleukin-2 or interleukin-21 immunotherapy, or transfers of spleen cells.
• Main results:
  • Tumour antigen was presented to T-cells in the draining lymph nodes even when tumours were small.
  • Tumour-specific killer T-cells were found in the draining lymph nodes of mice with small tumours, and their killing activity increased significantly as tumour burden increased.
  • When tumours were broken down into single cells and analysed, CD8+ cells made up only 3.4–5.2% of the cells in the tumour samples.
  • Inside tumours, there was no sign that target cells were being killed. The authors took this to suggest that killer T-cells in the tumour had lost the killing ability they had in the lymph nodes.
  • Tumour-specific CD8+ T-cells made up a much larger share of CD8+ T-cells inside tumours (up to 15.7%) than in draining lymph nodes.
  • Temporary antibody removal of CD4+ T-cells did not affect tumour growth rate. Mice that never had mature CD4+ T-cells (GK mice) had faster tumour growth.
  • Spleen cells transferred from tumour-bearing mice protected healthy recipient mice later challenged with tumour cells. Spleen cells from healthy mice did not prevent tumour growth.
  • Removing CD25+ cells with the antibody PC61 did not change the tumour growth rate compared with mice that were not depleted.
  • The authors stated that this CD25 depletion was done in established tumours. They contrasted this with other mesothelioma studies that gave the antibody before tumour inoculation or when tumours were very small.
  • When combined with interleukin-2 immunotherapy, CD25+ depletion abolished the effect of the treatment.
  • When combined with interleukin-21 immunotherapy, CD25+ depletion had no effect.
• The authors' conclusion: The authors concluded that Tregs are not potent regulators of anti-mesothelioma immunity in this model and that targeting these cells may not improve results.
• Limitations the authors state:
  • The authors could not rule out that the T-cells seen dividing in tumours had divided elsewhere and then moved into the tumour.
  • In the spleen-cell transfer experiments, what happened to any transferred regulatory cells is unknown.
  • Ethics committee conditions did not allow tumours to grow beyond 100 mm2.
  • The depleting antibodies came from rats and could only be used for 2 weeks.
  • Targeting CD25 to remove Tregs may also remove effector (immune-fighting) cells.

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Histopathology, Mesothelin, Chronic Inflammation, Immunotherapy.

Related studies

• Deliberately provoking local inflammation drives tumors to become their own protective vaccine site — C. Jackaman, A.M. Lew, et al. (2008)
• IL-2/CD40-driven NK cells install and maintain potency in the anti-mesothelioma effector/memory phase — C. Jackaman, S. Lansley, et al. (2012)
• Dual control of antitumor CD8 T cells through the programmed death-1/programmed death-ligand 1 pathway and immunosuppressive CD4 T cells: regulation and counterregulation — A.J. Currie, A. Prosser, et al. (2009)
• Accelerated cell cycle progression of human regulatory T cell-like cell line caused by continuous exposure to asbestos fibers — S. Lee, H. Matsuzaki, et al. (2017)
• Potent anti-tumor killing activity of the multifunctional Treg cell line HOZOT against human tumors with diverse origins — T. Inoue, Y. Tashiro, et al. (2011)
• Environmental factors as regulators and effectors of multistep carcinogenesis — T. Minamoto, M. Mai, et al. (1999)

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