Low-Dose Irradiation of the Gut Improves the Efficacy of PD-L1 Blockade in Metastatic Cancer Patients

The mechanisms governing the abscopal effects of local radiotherapy in cancer patients remain an open conundrum. Here, we show that off-target intestinal low-dose irradiation (ILDR) increases the clinical benefits of immune checkpoint inhibitors or chemotherapy in eight retrospective cohorts of cancer patients and in tumor-bearing mice. The abscopal effects of ILDR depends on dosimetry (=1 and =3Gy), and on the metabolic and immune host-microbiota interaction at baseline allowing CD8+ T cell activation without exhaustion. Various strains of Christensenella minuta selectively boosts the anti-cancer efficacy of ILDR and PD-L1 blockade, allowing emigration of intestinal PD-L1-expressing dendritic cells to tumor-draining lymph nodes. An interventional phase II study provides the proof-of-concept that ILDR can circumvent resistance to first- or second-line immunotherapy in cancer patients. Prospective clinical trials are warranted to define optimal dosimetry and indications for ILDR to maximize its therapeutic potential.