Low-dose irradiation of the gut improves the efficacy of PD-L1 blockade in metastatic cancer patients

Highlights•Off-target ILDR synergizes with anti-PD-L1 to eradicate non-irradiated tumors•The abscopal effects of ILDR depend on dosimetry (≥1 and ≤3 Gy) and volume•Gut composition governs the abscopal effects of ILDR combined with anti-PD-L1•ILDR and Christensenellaceae influence the emigration of intestinal mregDC to TdLNSummaryThe 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 depend on dosimetry (≥1 and ≤3 Gy) and on the metabolic and immune host-microbiota interaction at baseline allowing CD8+ T cell activation without exhaustion. Various strains of Christensenella minuta selectively boost 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 2 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.Graphical abstract