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 () and Sherene Loi ()
Additional contact information
Sathana Dushyanthen: Peter MacCallum Cancer Centre
Zhi Ling Teo: Peter MacCallum Cancer Centre
Franco Caramia: Peter MacCallum Cancer Centre
Peter Savas: Peter MacCallum Cancer Centre
Christopher P. Mintoff: Peter MacCallum Cancer Centre
Balaji Virassamy: Peter MacCallum Cancer Centre
Melissa A. Henderson: Peter MacCallum Cancer Centre
Stephen J. Luen: Peter MacCallum Cancer Centre
Mariam Mansour: Peter MacCallum Cancer Centre
Michael H. Kershaw: Peter MacCallum Cancer Centre
Joseph A. Trapani: Peter MacCallum Cancer Centre
Paul J. Neeson: Peter MacCallum Cancer Centre
Roberto Salgado: Institute Jules Bordet
Grant A. McArthur: Peter MacCallum Cancer Centre
Justin M. Balko: Vanderbilt-Ingram Cancer Centre and Vanderbilt University Medical Centre
Paul A. Beavis: Peter MacCallum Cancer Centre
Phillip K. Darcy: Peter MacCallum Cancer Centre
Sherene Loi: Peter MacCallum Cancer Centre

Nature Communications, 2017, vol. 8, issue 1, 1-18

Abstract: 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 downstream p38/JNK pathway activation. Taken together, our data suggest that although Ras/MAPK pathway inhibition can increase tumor immunogenicity, the negative impact on T-cell activity is functionally important. This undesirable impact is effectively prevented by combination with T-cell immune agonist immunotherapies resulting in superior therapeutic efficacy.

Date: 2017
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DOI: 10.1038/s41467-017-00728-9

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