Session Item

Stereotactic body radiation therapy (SBRT) has become the treatment of choice in several settings. However, ionizing radiation (IR) can damage healthy tissues surrounding the tumor and the resulting toxicities depend not only on the dose, but also on the extent of the volume treated. Few approaches have been tested concerning the reduction of irradiation volumes. Several preclinical and clinical studies support the rationale of combining RT with immune checkpoints inhibitors (ICI, notably anti-PD-1), which could result in tumor regression outside of the radiation field. We hypothetized that the combination of immune modulators, especially ICI, would prompt an antitumor effect not only at distant sites but also in non-irradiated volume within the same tumor mass, inducing an “in situ abscopal effect”. In addition, there has been a growing interest for low-dose RT within the past few years, based on the immunostimulatory properties of non-lethal ionizing radiation on the tumor immune microenvironment (TIME). Thus, using low-dose RT combined with high-dose partial RT appears to be a promising approach, especially in combination with immunomodulators. We studied the effects of IR volume modulation on the tumor response to SBRT in combination with ICIs and deciphered the spatiotemporal modulation of the TIME in these conditions.

Using a small animal SBRT platform, we have performed partial irradiations of MC38 subcutaneous tumors, irradiating a proportion of the tumor at the high dose of 16Gy and leaving the remaining volume either non-irradiated or irradiated at low dose. We combined such approach with immune checkpoint inhibitors as anti-PD1. Treatment efficacy was assessed by tumor growth and survival monitoring, and we analyzed the TIME by single-cell RNAseq, flow cytometry, cytokinome analysis and multiparametric immunohistology, comparing the irradiated regions with those non-irradiated (or IR a low dose) within the same tumor. We also performed partial tumor irradiations of murine orthotopic lung tumors.

Our results demonstrated a synergistic activity of partial IR and anti PD-1, which resulted in good tumor control. Partial tumor IR induced a reshaping of the TIME in both the irradiated and non-(or weakly) irradiated tumor volumes. Flow cytometry and scRNAseq analyses demonstrated a quantitative and qualitative modulation of the tumor immune populations. 

We obtained the proof of concept that partial tumor IR in combination with ICIs leads to a synergistic antitumor effect. Our analyses of the TIME in the partial IR setting contribute to a better understanding of the RT-induced immune modulations prompting also to better RT-immunotherapy combinations. Our results will thus contribute to the optimization of combined RT/immunotherapy treatments, by opening up new therapeutic options for tumors currently treated in a suboptimal manner and by limiting toxicities.