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Ionizing radiation is used to induce cytotoxicity in cancer, but it can also induce immune-modulatory effects, which may stimulate or inhibit anti-tumor immunity. In this prospective study, we aimed to further understand the immunomodulatory effects of SBRT through the longitudinal assessment of blood circulating cellular biomarkers during and after SBRT. The goal was to generate a hypothesis for the optimal dose and fractionation for combining SBRT with standard immune checkpoint inhibitor (ICI) drugs for NSCLC.

50 patients with eraly stage NSCLC were prospectively included. Blood samples were obtained just before treatment (RT_baseline), 1 day after the first fraction of SBRT (RT_day1), at the end of SBRT (RT_end) and at follow-up after 6 weeks (RT_FU1) and 4.5 months after the start of the treatment (RT_FU2). Patients received SBRT using the following fractionation/dose regimens: 3 x 18.75 Gy (n=21), 5 x 10 Gy (n=6), 8 x 7.5 Gy (n=21) and 12 x 5.5 Gy (n=1), with a minimum biological effective dose of 100 Gy.

We found a statistically significant increase in the fraction of expanding (Ki-67⁺) CD8⁺ and CD4⁺ T-cells, in both in PD1⁺ and PD1^– subpopulations, after SBRT (RTend) compared to baseline, and a decrease to baseline levels after 6 weeks (RT_FU1). These results remained significant in the fractionation/dose subgroup analysis for the patients treated with 8 x 7.5 Gy but not for those treated with 3 x 18.75 Gy.

Study results indicate that SBRT results in significant systemic increase in activated T cells, which is most prominent at the end of treatment, and that lower doses per fraction might be more effective in inducing this immunomodulatory effect than the higher ones. Based on these data, we suggest that adding ICIs in NSCLC would be more effective applied at the end of SBRT performed with lower doses per fraction.