Black Holes in TIME: the Effect of GRID Radiation on the Tumor-Immune Micro-environment
Tumor-immune interactions shape a developing tumor and its tumor immune microenvironment (TIME) resulting in either well infiltrated, immunologically inflamed ‘hot’ tumor beds, or ‘cold’ immune deserts with low levels of infiltration that are suppressive in nature. The pre-treatment immune state of the TIME is associated with treatment outcome; immunologically hot tumors generally exhibit better responses to radio- and immunotherapy than cold tumors. However, radiotherapy is known to induce paradoxical immunological consequences, resulting in both immunostimulatory and inhibitory responses. In fact, it is thought that the radiation-induced tumoricidal immune response is curtailed by subsequent applications of radiation. It is thus conceivable that spatially fractionated radiotherapy (SFRT), administered through GRID blocks to create areas of low or high dose exposure, may protect regions of the tumor immune microenvironment, thereby preserving anti-tumor immune responses. We use an agent-based model of tumor-immune interaction to investigate the therapeutic utility of SFRT. We evaluate the immunological consequences of various GRID architectures, radiation doses and dose scheduling, to identify which GRID architectures result in superior immune infiltration for each pre-treatment immune state. Additionally, we investigate TIMEs for which SFRT may be better suited, in an immune context, than conventional radiotherapy.