Journal article

Agonist immunotherapy restores T cell function following MEK inhibition improving efficacy in breast cancer

Sathana Dushyanthen, Zhi Ling Teo, Franco Caramia, Peter Savas, Christopher P Mintoff, Balaji Virassamy, Melissa A Henderson, Stephen J Luen, Mariam Mansour, Michael H Kershaw, Joseph A Trapani, Paul J Neeson, Roberto Salgado, Grant A McArthur, Justin M Balko, Paul A Beavis, Phillip K Darcy, Sherene Loi

NATURE COMMUNICATIONS | NATURE PUBLISHING GROUP | Published : 2017

Abstract

The presence of tumor-infiltrating lymphocytes in triple-negative breast cancers is correlated with improved outcomes. Ras/MAPK pathway activation is associated with significantly lower levels of tumor-infiltrating lymphocytes in triple-negative breast cancers and while MEK inhibition can promote recruitment of tumor-infiltrating lymphocytes to the tumor, here we show that MEK inhibition adversely affects early onset T-cell effector function. We show that α-4-1BB and α-OX-40 T-cell agonist antibodies can rescue the adverse effects of MEK inhibition on T cells in both mouse and human T cells, which results in augmented anti-tumor effects in vivo. This effect is dependent upon increased downst..

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Grants

Awarded by NHMRC



Awarded by National Breast Cancer Foundation


Funding Acknowledgements

We thank Ralph Rossi, Vicki Milovac, and Sophie CurcioPeter from MacCallum Cancer Centre (PMCC) FACS facility. Kaushalya Amarasinghe; PMCC Animal facility and technicians, PMCC Cytotoxic suite, PMCC Bioinformatics core. Laura Kilpatrick and Amy Rogers (Cancer Cell Death Laboratory) for providing the OT-I cells. This work was funded by project grants from the National Breast Cancer Foundation (NBCF), Australia and the National Health and Medical Research Council (NHMRC). S.L. is supported by Cancer Council, Victoria, Australia and the Breast Cancer Foundation (BCRF), N.Y. P.A.B. is supported by Fellowships (ID# PF-14-008). P.K.D. and M.H.K. are supported by NHMRC Senior Research Fellowships (APP1041828 and APP1058388), respectively.