A probiotic bacterium modulates antitumour γδ T-cell responses in lung cancer

The link between the intestinal microflora and cancer outcomes has been recognized for over a decade. Several recent studies have demonstrated that the gut microbiome is associated with the efficiency of T-cell checkpoint blockade therapy for cancer, raising interest in strategies to harness this effect via consumption of live microorganisms (probiotics). The probiotic Clostridium butyricum strain MIYAIRI 588 (CBM588) improves response rates and overall survival in patients receiving immune checkpoint inhibitor (ICI) therapy for non-small cell lung cancer and metastatic renal cell carcinoma but the mechanism underlying this benefit remains unclear. Here, we show that CBM588 spores induce a population of Vγ9Vδ2 T-cells from the peripheral blood of healthy donors and lung cancer patients. A subset of these T-cells responded to, and directly lysed, cancer cell lines via a butyrophilin 3A-dependent mechanism. In patients taking CBM588 alongside checkpoint blockade, using samples from a cohort of 38 patients, peripheral blood Vδ2 + T-cells expressed the activation marker CD69 more frequently than in those receiving checkpoint blockade alone and the frequency of Vδ2 + CD69 + cells increased following initiation of CBM588 treatment (p = 0.0041). Pleural effusions from patients receiving ICI with CBM588, although available from only three individuals, also showed a notable shift in the local γδ T-cell compartment from the expected Vδ1 dominance towards Vδ2 cells, suggesting altered recruitment or retention of Vδ2 cells at the tumour site. Across the patient cohort, higher post-treatment frequencies of CD69 + Vδ2 T-cells were associated with improved survival and more favourable clinical outcomes. These findings provide a potential mechanism by which manipulation of the intestinal microflora might contribute to cancer prognosis through effects on immune effector cells with intrinsic anticancer properties.