Immune Manipulation Boosts Radiation Therapy

High-dose radiation therapy kills tumor cells. It also stimulates the immune system to attack cancer cells that escape radiation therapy, within and outside the field of treatment.

But this beneficial tumor-cell-killing response is short-lived.

In the February 2014 issue of the Journal of Clinical Investigation, researchers from the University of Chicago, working with a mouse tumor model, describe a novel way to extend this beneficial post-radiation immune response.

Ralph Weichselbaum, MD

By selectively blocking an immune modulator produced in response to radiation therapy—known as programmed death-ligand 1 (PD-L1)—the researchers were able to sustain the desired after-effects of intensive radiation therapy.

“We showed that PD-L1 secretion was linked to the fairly rapid immune suppression seen after radiation therapy,” said study author Ralph Weichselbaum, MD, the D.K. Ludwig professor and chairman of radiation and cellular oncology at the University of Chicago. “By inhibiting PD-L1, we were able to prevent this, to take the brakes off of the radiation-induced immune response.”

Yang-Xin Fu, MD, PhD

The combination of anti-PD-L1 and radiation therapy proved “much more effective than radiation alone,” said co-author Yang-Xin Fu, MD, PhD, professor of pathology at the University of Chicago. “Anti-PD-L1 amplified radiation’s antitumor effect.”

The researchers were able to map out some key elements of the chain of events behind anti-PD-L1’s benefits. They showed that soon after radiation therapy, surviving cells in the treated area express high levels of PD-L1. Radiation also triggers an influx of cells, known as myeloid-derived suppression cells or MDSCs. These cells promote tumor-cell survival and tamp down the desired immune response. This allows tumor regrowth after treatment.

But adding high doses of anti-PD-L1, a drug currently in clinical trials against lung and other cancers, reverses suppression of the immune system and reactivates the T cells that kill MDSC and tumor cells – thus restoring the immune system’s anti-tumor efforts.

The National Institutes of Health, the Ludwig Foundation and the Folgia Foundation funded this research. Additional authors include Yang-Xin Fu, Liufu Deng, Hua Liang, Byron Burnette, Michael Beckett and Thomas Darga, all from the University of Chicago.

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