Local effector failure in mesothelioma is not mediated by CD4⁺CD25⁺Treg cells

¹ University of Western Australia, School of Medicine and Pharmacology, Perth, Western Australia, Australia, 6009
² Curtin University, School of Biomedical Sciences, Bentley, Perth, Western Australia, Australia, 6102;; and Western Australia Biomedical Research Institute, Bentley, Perth
³ Walter and Eliza Hall Institute, Melbourne, Victoria, Australia 3050
⁴ Curtin University, School of Biomedical Sciences, Bentley, Perth, Western Australia, Australia, 6102;; University of Western Australia, School of Medicine and Pharmacology, Perth, Western Australia, Australia, 6009; and Western Australia Biomedical Research Institute, Bentley, Perth

	Abstract

Aims: To define the point at which mesothelioma T cell responses fail in order to design better immunotherapies. Approach: We used a murine model of mesothelioma that was established with asbestos, and 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. Results: The mesothelioma microenvironment contains stromal elements including dendritic cells, effector CD8⁺ and CD4⁺ T cells, and CD4⁺ T regulatory cells (Tregs), 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⁺ CTL 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 Treg 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 IL-2 or IL-21 immunotherapy. Conclusions: Treg cells are not potent regulators of anti-mesothelioma immunity and targeting these cells may not improve results.