Editors' ChoiceCancer

An old inhibitor with new tricks

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Science Translational Medicine  16 Mar 2016:
Vol. 8, Issue 330, pp. 330ec43
DOI: 10.1126/scitranslmed.aaf6181

Programmed death ligand 1 (PD-L1) immunotherapy, which overcomes T cell immunosuppression in the tumor microenvironment, has made headway in slowing the growth of multiple cancer types. Nevertheless, many tumors are only modestly responsive to this therapy. The next step in enhancing antitumor immunity is likely combination therapy incorporating PD-L1 inhibition along with other methods of treatment. Inhibition of mitogen-activated protein kinase (MAPK) kinase (MEK), a key signaling pathway promoting tumor cell proliferation, has also shown encouraging results in clinical trials for some cancer types, such as melanoma and non–small cell lung cancer.

Despite promising results, neither MEK nor PD-L1 inhibition usually results in complete tumor regression. Consequently, Ebert et al. approached this dilemma by combining the two therapies. Using an orthotopic colon cancer model, the group showed that MEK inhibition slowed the rapidly growing tumors for several weeks, but later the tumors progressed. Upon MEK inhibition, the researchers noticed an increase in tumor infiltration by CD8+ T cells, along with a 50% decrease in expression of the T cell immunosuppressive receptor PD-1 by these cells. Furthermore, they unexpectedly found that tumor-associated CD8+ T cells in mice treated with MEK inhibitors began to express markers of an antitumor phenotype with much higher frequency than controls. When the researchers examined the CD8+ T cell activity in vitro, they found that MEK inhibition promoted CD8+ T cell survival by decreasing exhaustion and down-regulating apoptotic pathways but did not affect the tumor cell killing function. These results suggest that an additional therapy, such as anti–PD-L1, could down-regulate inhibitory mechanisms, resulting in T cell activation and enhanced tumor lytic activity. Thus, the team combined the two therapies in tumor-bearing mice and showed enhanced antitumor efficacy compared with anti-PD-L1 therapy alone.

This work suggests that promising treatments that may not be completely effective as monotherapy should not be overlooked. New combinations of therapeutic approaches may indeed be the key to tumor regression.

P. J. R. Ebert et al., MAP kinase inhibition promotes T cell and anti-tumor activity in combination with PD-L1 checkpoint blockade. Immunity 10.1016/j.immuni.2016.01.024 (2016). [Abstract]

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