UCSD researchers identify molecular switch in cancer


Immunotherapeutics, which target the immune system, have recently found their place in cancer therapy--an example being T cell checkpoint inhibitors. In some aggressive cancers, however, the cancer finds a way to avoid this suppression. Researchers have recently found a key player that might be regulating this process, and by blocking this molecule they can increase the sensitivity of the tumor to anticancer drugs.

The research was headed up by Judith Varner from UC San Diego; she and her team published the results in the journal Nature.

The immune system is able to distinguish between normal cells in the body and those it sees as “foreign” and subsequently attacks these foreign cells while leaving the healthy cells intact. For this to work effectively, it uses “checkpoints," molecules on certain immune cells that need to be activated (or inactivated) to start an immune response.

In some cases, cancer cells can hijack these checkpoints to avoid being attacked by the host’s immune system. As such, drugs that target these checkpoints hold huge therapeutic value. Cancer may respond however by stimulating macrophages (early response white blood cells) to produce anti-inflammatory cytokines, which do the reverse, dampening the immune response against the cancer.

To combat this, Varner and colleagues found a key enzyme in macrophages called PI3Kγ that signals to promote immune suppression by inhibiting antitumor T cells. Experimentally, they blocked PI3Kγ from functioning and could kick-start the immune system into action, reducing tumor growth in a mouse model. It also showed a synergistic effect when combined with classical anticancer drugs.

"Recently developed cancer immunotherapeutics, including T cell checkpoint inhibitors and vaccines, have shown encouraging results in stimulating the body's own adaptive immune response," said co-author Ezra Cohen in a statement. "But they are effective only on a subset of patients, probably because they do not alter the profoundly immunosuppressive microenvironment created by tumor-associated macrophages. Our work offers a strategy to maximize patient responses to immune therapy and to eradicate tumors.”

Varner and her group plan to test this “molecular switch” in cancer, as well as other chronic diseases such as Alzheimer’s and Crohn’s disease, with a view to improve the immune suppression in these life-threatening diseases.