Instead of thwarting immunotherapy, radiotherapy might enhance its cancer-fighting effects, experiments in mice show, by increasing the population of CD8+ T cells.

New research reveals that radiation increases the power of immunotherapy to combat cancer, and provides a possible explanation for this effect.

Researchers have long thought that radiation impairs the immune system, but many of the studies supporting that conclusion exposed subjects to extensive radiation fields or even full-body radiation, says Andrew Sharabi, MD, PhD, of the Department of Radiation Oncology and Molecular Radiation Science at Johns Hopkins in Baltimore, MD.

Evidence has been accumulating that focused radiation that doesn't harm the bone marrow can increase immunotherapy's effectiveness in treating cancer. Two 2012 case studies, for instance, reported that radiation enhanced the potency of immunotherapy in melanoma patients. Although studies pairing these therapies are under way, researchers haven't confirmed that the approach is beneficial, and the mechanism by which radiation could augment immunotherapy isn't clear.

To address these questions, a team led by Sharabi and medical oncologist Charles Drake, MD, PhD, of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, implanted mice with melanoma and breast cancer cells. The researchers then injected the animals with antibodies that block CTLA-4 or PD-1, two immune checkpoint proteins. Some mice also received stereotactic radiation therapy that hits only the tumor and a few millimeters of neighboring tissue.

Radiation and immunotherapy increased the animals' survival and shrank their tumors more than either treatment alone, the researchers revealed last month at the American Society of Radiation Oncology meeting in San Francisco, CA. For example, breast tumors in mice that received both kinds of therapy were less than one sixth the size of tumors in animals that received only immunotherapy.

The researchers also found that the combination of radiation and immunotherapy increased the number of CD8+ T cells targeted against tumor antigens in the animals' draining lymph nodes. “The study establishes that tumor-specific immune responses can be induced by combined treatment in this model system,” says Sharabi.

“The ultimate goal is to treat with local radiation and get a systemic effect that works against metastases,” adds Drake. An experiment in which the researchers implanted cancer cells on both sides of the mice and then gave them immunotherapy had little impact on the tumors on either side. However, when the researchers irradiated one side of the animals, tumors on both sides shrank, suggesting that radiation produces this systemic effect.

The results suggest that radiation boosts immunotherapy through a mechanism called cross presentation, which occurs when radiation kills tumor cells, dispersing their antigens. Dendritic cells pick up the antigens and use them to alert CD8+ T cells to the tumor's presence.

Further animal studies will help researchers determine the optimal timing and dose of radiation, Sharabi says.

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