June 21, 2021, NEW YORK – A study led by Ludwig Chicago Co-director Ralph Weichselbaum and researcher Hua Laura Liang found that combining radiotherapy with all-trans retinoic acid (ATRA), a derivative of vitamin A, significantly inhibits the growth of not only locally irradiated tumors but also distal tumors not treated with radiation in animal models of cancer. The findings were reported June 11 in Science Immunology.
ATRA is thought to play a role in the development and differentiation of immune-related cells and is used to treat acute promyelocytic leukemia, an aggressive blood cancer.
With radiation alone, inflammation in some tumors prompts monocytes (a type of white blood cell) to rush to the scene to repair damage. Some of these monocytes are reprogrammed into myeloid-derived suppressor cells (MDSCs), which promote tumor growth and suppress cancer-targeting T cells.
ATRA disrupts these events. When irradiated, the tumor’s pre-existing T cells start producing interferon gamma (IFN-γ), which helps activate the immune response. Together, IFN-γ and ATRA convert harmful MDSCs into helpful inflammatory macrophages that produce factors to further inflame the tumor microenvironment. This calls in more T cells, starting the cycle anew.
Notably, the combination treatment activated not only CD8+ T cells, which kill cancer cells, but also CD4+ T cells that have a key role in antitumor immunity. Both types of T cells produced elevated levels of IFN-γ, which mediates cancer cell killing.
Of significance was the increased number of both CD8+ and CD4+ T cells in not only locally irradiated tumors but in distal untreated tumors as well, a phenomenon known as the abscopal effect.
The team was able to further suppress the growth of distal tumors by adding to the combination treatment a PD-L1 blockade antibody, an immunotherapy that drives the T cell targeting of tumor cells. “The addition of a PD-L1 blockade produced a much stronger abscopal effect,” said Weichselbaum, who is also chair of the Department of Radiation and Cellular Oncology at the University of Chicago.
Liang is also a Research Assistant Professor at the University of Chicago.
The release from which this summary is derived can be found here.