Novel mechanism by which tumors evade immunotherapies discovered

A study, recently published in Nature Communications, led by Benoit Van den Eynde (Ludwig Institute for Cancer Research, UK) demonstrated that there is a novel mechanism used by tumors leading to early T cell apoptosis, preventing effective immune attack.

“Immunotherapy has been delivering some impressive results, but only for a fraction of patients,” Van den Eynde discussed. “Now the million dollar question is, what can we do to improve the proportion of patients that respond to these treatments? There are a variety of mechanisms of immune resistance that operate in the tumor. This is what we are addressing in our studies.”

The effects of immunotherapies are usually investigated by transplanting tumors into genetically suitable mice. These tumors do not accurately reflect how cancers evolve mechanisms to evade the immune response in humans.

“That’s what happens in clinical situations and that’s what we want to model in our studies,” commented Van den Eynde. “If you just inject a million tumor cells in a mouse to create a tumor, you do not recapitulate this process–the interplay between the host and the tumor, the immune response that starts but then gets dampened by the tumor, or the tumor’s ultimate escape from that response.”

To combat this problem, in this study, melanoma tumors were induced in mice and the effects of multiple immunotherapies were evaluated including adoptive T cell therapy (ACT), which was unsuccessful in induced tumor models.

In both induced and transplanted models ACT successfully delivered T cells to the tumor; however, the fate of the T cells in the different models differed. “We found that in the induced tumors, about half of the T cells were already apoptotic 4 days after ACT,” explained Van den Eynde. “This explained why they did not persist: The induced tumor behaves like a sink for these T cells. That does not happen in the transplanted tumors.”

The cancer cells in both induced and transplanted tumors were the same, so to discover what might be causing the T cell apoptosis, researchers compared noncancerous cells. They demonstrated that polymorphonuclear myeloid-derived suppressor cells were exclusively present in induced tumors and express high levels of FAS-ligand, which bind to T cells, inducing apoptosis.

The researchers confirmed that these cells play a role in T cell inhibition by depleting polymorphonuclear myeloid-derived suppressor cells from the tumors or by blocking FAS-ligand binding restored the T cell ability to kill induced tumors. “This is a novel mechanism by which these cells suppress immune responses in tumors,” concluded Van den Eynde. “Targeting FAS-ligand could be a good adjunct therapy to boost the effects of immunotherapeutic drugs.”

Sources:

Ludwig press release; Zhu J, Powis de Tenbossche C, Cané S et al. Resistance to cancer immunotherapy mediated by apoptosis of tumor-infiltrating lymphocytes doi:10.1038/s41467-017-00784-1 Nat. Commun. (2017).