Effect of anti-CTLA4 (tremelimumab) on the immunomodulatory activity of t regulatory cells


Year:

Session type:

Sameena Khan, Debbie Burt, Christy Ralph, Robert Hawkins, Eyad Elkord

Paterson Institute for Cancer Research, University of Manchester, UK

Abstract

Background

Cytototoxic T Lymphocyte Antigen-4 (CTLA-4) blockade with tremelimumab has shown activity against metastatic melanoma, hormone refractory prostate cancer and other malignancies. However, the exact mechanism of action remains to be elucidated. Two mechanisms have been proposed; either by acting through inhibition/ depletion of CD4+CD25+ T regulatory cells (Treg) which have constitutive expression of CTLA-4, or activation of CD4+CD25- T effector cells (Teff) and rendering them more resistant to Treg suppression.

Method

Treg and Teff cells were isolated by magnetic or fluorescence- activated cell sorting. The effect of tremelimumab on Treg suppressive activity was examined using in vitro suppression assays. Proliferation and cytokine release in the absence or presence of tremelimumab were measured using 3H-thymidine or CFSE-based proliferation assays and flow cytometric intracellular cytokine staining, respectively.

Results

Teff cells showed higher dose-dependant proliferative responses in the presence of tremelimumab. In addition, tremelimumab abrogated Treg suppressive activity especially at lower Treg:Teff ratios. In the presence and IL-2- secreting CD4gof tremelimumab, proportions of IFN+ and CD8+ T cells were increased in response to polyclonal activation. Effect of tremelimumab on enhancing tumour- specific T cell responses is currently under investigation.

Conclusion

Tremelimumab enhances cytokine release and proliferation of T cells, and inhibits Treg suppressive activity; whether these activities are modulated by Treg inhibition or Teff activation require further investigation.