par Dushyanthen, Sathana;Kershaw, Michael M.H.;Trapani, Joseph J.A.;Neeson, Paul P.J.;Salgado, Roberto;McArthur, Grant A;Balko, Justin J.M.;Beavis, Paul P.A.;Darcy, Phillip K;Loi, Sherene 
;Teo, Zhi Ling;Caramia, Franco;Savas, Peter;Mintoff, Christopher Paul;Virassamy, Balaji;Henderson, Melissa M.A.;Luen, Stephen;Mansour, Mariam
Référence Nature communications, 8, 1, 606
Publication Publié, 2017-12
;Teo, Zhi Ling;Caramia, Franco;Savas, Peter;Mintoff, Christopher Paul;Virassamy, Balaji;Henderson, Melissa M.A.;Luen, Stephen;Mansour, MariamRéférence Nature communications, 8, 1, 606
Publication Publié, 2017-12
Article révisé par les pairs
| Résumé : | 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. |
