Understanding the effects of certain targeted therapies on antitumour immunity is necessary to design combined interventions for more effective cancer treatment.

In the past, data have shown that trametinib, an FDA-approved MEK inhibitor routinely administered to patients with melanoma and currently being studied to treat a number of other types of cancer, inhibits T cell responses in vitro, but is effective in some tumour models in vivo.

Scientists at The Wistar Institute recently discovered how this drug boosts antitumour activity and slows tumour progression, even if it fails to directly stop tumour cell proliferation.

Study results were published in the journal Cancer Research.

When small molecule kinase inhibitors -- a class of drugs designed to target specific mutations and proteins related to cancer while sparing healthy cells without these mutations -- started being approved for different types of cancer, the laboratory of José R. Conejo-Garcia, M.D., Ph.D., professor in the Wistar, initiated a project to understand the effects of these targeted therapies on immune response.

"We realised that most small kinase inhibitors in the pipeline targeted pathways that are important for the function of immune cells," Conejo-Garcia said. "However, they had been primarily tested in vitro against tumour cells or in immunodeficient animals at best. Very little was known about the consequences of using these interventions on spontaneous or immunotherapeutically boosted antitumour immunity."

In this study, Conejo-Garcia and colleagues found that trametinib controls tumour progression by halting the mobilization of myeloid-derived suppressor cells (MDSCs), a set of immune cells that have been linked to making tumours resistant to treatment.

This reduced the level of immune suppression in the tumor, allowing anti-tumour T cells to target the tumour.

In fact, the effectiveness of trametinib is dependent on the activity of these anti-tumour T cells, despite its direct inhibitory effects on this tumour cell compartment, which are largely rescued by certain cytokines present at tumour beds.

Although trametinib failed to directly inhibit tumour cell proliferation, its combined effects on multiple immune and nonimmune compartments boosted antitumour immunity in vivo in tumour-bearing hosts and significantly delayed malignant progression.

"Understanding the effects of trametinib on antitumour immunity is urgently needed to design the sequence of rational combinatorial interventions that include emerging and future anticancer immunotherapies," Conejo-Garcia said. "Our findings demonstrate that trametinib could be combined with existing immunotherapeutic agents in at least tumors that mobilize a significant amount of immunosuppressive myeloid cells."

Source: Cancer Research