Radiation therapy causes a STING and MyD88-independent upregulation of CD80 and CD86 in macrophages and monocytes that limits tumor control.

In preclinical models, optimum tumor control by radiation therapy incorporates CD8 T cell control of residual cancer cells. Tumor control by these CD8 T cells is negatively regulated by myeloid and T regulatory cell expansions in the tumor following radiation treatment. We demonstrate using ex vivo 3D tumor models and novel in vivo cell tracking models that radiation results in upregulation of the costimulatory molecules CD80 and CD86 on tumor macrophages and on monocytes that enter the tumor following radiation. This regulation of CD80 is not dependent on adjuvant signaling via MyD88 or STING in the myeloid cells. While we would anticipate that CD80 and CD86 would have a positive impact on anti-tumor immunity, we demonstrate that blockade of CD80 and CD86 signaling limits CD4 infiltrates in tumors and prevents the Treg expansion caused by radiation treatment. Importantly, this treatment results in improved tumor control following radiation therapy. These data link the inflammatory activation of myeloid cells in irradiated tumors to the Treg expansion following radiation and ensuing suppression of anti-tumor immunity.