Early peripheral Treg expansion after SBRT combined with low-dose radiotherapy to predict subsequent immune checkpoint inhibitor responses in patients with metastatic lung or gastrointestinal cancers.

Abstract

2652 Background: This study aims to explore the potential therapeutic advantages of combining stereotactic body radiation therapy (SBRT) and low-dose radiotherapy (LDRT) prior to immune checkpoint inhibitor (ICI) treatment for metastatic lung or gastrointestinal cancers, to induce an immune-favoring tumor microenvironment. Methods: Patients with metastatic cancer and three or more measurable lesions scheduled for ICI therapy were enrolled in this study. Treatment consisted of three SBRT doses of 8–10 Gy to the main target lesion and LDRT (2–3 Gy) for other lesions. Patients without evidence of disease progression within 6 months after the first dose of ICI were defined as responders, while others were classified as non-responders. Peripheral blood samples obtained before SBRT/LDRT (W0), 1 week after SBRT/LDRT but prior to ICI initiation (W1), and 4 weeks after SBRT/LDRT (W4) were analyzed using multi-color flow cytometry. This trial has been registered at cris.nih.go.kr (registration number:KCT0005879). Results: Among the 13 enrolled patients (lung 9, gastrointestinal 4), samples from 4 responders and 7 non-responders were analyzed initially, revealing a median progression-free survival of 22.2 months for responders and 3.1 months for non-responders. The fold change in the proportion of regulatory (Foxp3 + CD25 + ) CD4 + T cells (Tregs) among total CD4 + T cells at W1 compared to W0 (Treg/CD4–FC W1/W0 ) was lower in responders than in non-responders (0.66 vs. 1.22; P = 0.08). Furthermore, the fold change in the proportion of suppressive Foxp3 hi CD45RA + Tregs among Tregs at W1 compared to W0 (Fr.II/Treg–FC W1/W0 ) was significantly lower in responders than in non-responders (0.80 vs. 1.18; P = 0.047). This difference was no longer evident after one cycle of ICI, as Treg/CD4–FC W4/W0 (1.15 vs. 0.86; P = 0.46) and Fr.II/Treg–FC W4/W0 (1.06 vs. 1.33; P = 0.18) were not significantly different between responders and non-responders. Conclusions: We investigated circulating T cell modulation and its potential as a biomarker which revealed early expansion of Tregs in peripheral blood after SBRT/LDRT is associated with suboptimal response to ICIs in patients with metastatic cancers. Clinical trial information: KCT0005879 .