Type-1-cytokines synergize with oncogene inhibition to induce tumor growth arrest

Both targeted inhibition of oncogenic driver mutations and immune-based therapies show efficacy in treatment of patients with metastatic cancer but responses are either short-lived or incompletely effective. Oncogene inhibition can augment the efficacy of immune-based therapy but mechanisms by which these two interventions might cooperate are incompletely resolved. Using a novel transplantable BRAFV600E-mutant murine melanoma model (SB-3123), we explore potential mechanisms of synergy between the selective BRAFV600E inhibitor vemurafenib and adoptive cell transfer (ACT)-based immunotherapy. We found that vemurafenib cooperated with ACT to delay melanoma progression but surprisingly did not enhance tumor infiltration or effector function of endogenous or adoptively transferred CD8+ T cells as previously observed. Instead, we found that the T cell cytokines IFN-gamma and TNF-alpha synergized with vemurafenib to induce cell cycle arrest of tumor cells in vitro. This was recapitulated in vivo as continuous vemurafenib administration was required to delay melanoma progression following ACT. The unexpected finding that immune cytokines synergize with oncogene inhibitors to induce growth arrest have major implications for understanding cancer biology at the intersection of oncogenic and immune signaling and provides a basis for design of combinatorial therapeutic approaches for patients with metastatic cancer.

12

Acquavella N, Clever D, Yu Z, Roelke-Parker M, Palmer DC, Xi L, Pflicke H, Ji Y, Gros A, Hanada K, Goldlust IS, Mehta GU, Klebanoff CA, Crompton JG, Sukumar M, Morrow JJ, Franco Z, Gattinoni L, Liu H, Wang E, Marincola F, Stroncek DF, Lee CC, Raffeld M, Bosenberg MW, Roychoudhuri R, Restifo NP