Agonist immunotherapy restores dysfunctional T cells following MEK inhibition and improves therapeutic efficacy Sathana Dushyanthen1, Paul A Beavis1*, Phillip K Darcy1,2*, Sherene Loi1,2* 1Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; 2Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, 3010, Australia *Equal contributions, co-corresponding authors
Previously we have shown that tumor infiltrating lymphocytes (TILs) are an important prognostic factor in triple negative breast cancer (TNBC); where their presence is associated with improved survival1. Ras/MAPK pathway activation is associated with significantly lower levels of TILs in TNBC and whilst MEK inhibition can promote recruitment of TILs to the tumor, here we show that MEKi adversely affects early onset T cell effector function. Our studies2,3 have demonstrated that the MEK targeted inhibitor (trametinib) increased immunogenicity (MHCI/II,) of tumors and reduced tumor growth. However, whilst MEK inhibition effectively inhibited tumor growth, blockade of this pathway triggered adverse inhibitory effects on crucial ERK signaling in immune cells, thus reducing their functional activity and overall efficacy of this treatment. We have previously shown that combining anti PD-1 with trametinib can enhance anti-tumor effects2. In the current study immune agonists anti-4-1BB or anti-OX-40 were combined with trametinib in order to recover immune cell function through rescue of T cell function independently of the MEK1/2 pathway3. These agonists restored T cell proliferation (Ki67), cytokine production (IFNy) and redirected signaling through p38/JNK activation following trametinib treatment, leading to enhanced TIL function and more effective anti-tumor immune responses in vivo. Accordingly, this data suggests that immune agonists with anti-PD-1 checkpoint blockade may be an effective strategy as the combination can directly overcome T cell suppression induced by MEK inhibition. As such, we propose that combining trametinib with agonistic immunotherapy could be a promising strategy in the clinic for TNBC patients.
Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F, Rouas G, Francis P, Crown JP, Hitre E, de Azambuja E, Quinaux E, Di Leo A, Michiels S, Piccart MJ, Sotiriou C. Journal of Clinical Oncology. 2013 Mar 1;31(7):860-7
Loi S, Dushyanthen S, Beavis PA, Salgado R, Denkert C, Savas P, Combs S, Rimm DL, Giltnane JM, Estrada MV, Sánchez V, Sanders ME, Cook RS, Pilkinton MA, Mallal SA, Wang K, Miller VA, Stephens PJ, Yelensky R, Doimi FD, Gómez H, Ryzhov SV, Darcy PK, Arteaga CL, Balko JM. Clinical Cancer Research. 2016 Mar 15;22(6):1499-509
Dushyanthen S1. Teo L Z1,2, Caramia F1, Savas P1, Mintoff C1,Virassamy B1, Henderson A M1, Luen J S1, Mansour M1, Kershaw H M1,2, Trapani A J1,2, Neeson J P1,Salgado R 3, McArthur A G1, Balko M J4, Beavis A P1,2*, Darcy K P1,2*, Loi S1,2*. Nature Communications, 2017, Sept 8; 606.
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