Radiation-Induced Equilibrium Is a Balance between Tumor Cell Proliferation and T Cell–Mediated Killing

Abstract

Local failures following radiation therapy are multifactorial and the contributions of the tumor and the host are complex. Current models of tumor equilibrium suggest that a balance exists between cell birth and cell death due to insufficient angiogenesis, immune effects, or intrinsic cellular factors. We investigated whether host immune responses contribute to radiation induced tumor equilibrium in animal models. We report an essential role for immune cells and their cytokines in suppressing tumor cell regrowth in two experimental animal model systems. Depletion of T cells or neutralization of interferon-gamma reversed radiation-induced equilibrium leading to tumor regrowth. We also demonstrate that PD-L1 blockade augments T cell responses leading to rejection of tumors in radiation induced equilibrium. We identify an active interplay between tumor cells and immune cells that occurs in radiation-induced tumor equilibrium and suggest a potential role for disruption of the PD-L1/PD-1 axis in increasing local tumor control.

Irradiation and anti–PD-L1 treatment synergistically promote antitumor immunity in mice

“…These results suggest that anti-PD-L1 treatment not only improves the effects of IR on the primary tumor, but also mediates an abscopal effect on distant tumors. Altogether, these results demonstrate that CD8 + T cells are necessary for the therapeutic effects of IR plus anti-PD-L1 therapy and are in agreement with our previous observations using IR as a single modality (2,3,31). Next, we hypothesized that the combination of IR and anti-PD-L1 treatment enhances tumor antigen-specific T cell responses.…”

From DNA Damage to Nucleic Acid Sensing: A Strategy to Enhance Radiation Therapy

“…Costimulatory and coinhibitory receptors play a dominant role in T-cell activation, differentiation, and function (60). It is reasonable to argue that the agonists and antagonists targeting costimulators/inhibitors are able to increase T-cell function or relieve T-cell inhibition during radiotherapy (14). We have found that the effect of radiation-induced immune-mediated tumor regression gradually diminished as tumor growth continued to progress.…”

“…Although radiation is effective in producing tumor regression, the tumors may eventually recur even after a prolonged stable or dormant phase (14). Multiple resistance mechanisms facilitate tumor relapse during the inflammatory response that occurs after radiation.…”

“…Radiation-induced equilibrium or dormancy, a common feature in both clinical and preclinical cases, is also a balance between tumor cell proliferation and T-cell-mediated killing (14). Ablative radiation increases T-cell priming in draining lymphoid tissues and reduction of the primary tumor or distant metastasis in a CD8…”

“…Stereotactic body radiotherapy (SBRT) is a technique that takes advantage of the technologic advances in image guidance and radiation dose delivery (3). SBRT directs ablative doses (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) to tumors with acceptable toxicity that was not previously achievable (3). The tumor response to radiation includes DNA damage, modulation of signal transduction, and alteration of the inflammatory tumor microenvironment (1).…”