High Serum 3-IAA Improves Chemotherapy Response in Pancreatic Cancer

Less than half of patients with metastatic pancreatic ductal adenocarcinoma (PDAC) respond to standard-of-care chemotherapy. Genetic alterations do not fully explain these differences in therapy response, suggesting that environmental factors, like intestinal microbiota, may be potential mediators of efficacy. Tintelnot and colleagues evaluated how microbiota or dietary habits can affect chemotherapy efficacy in patients with PDAC and showed distinct microbiota between responder (R) and nonresponder (NR) patients. Transplantation of microbiota from these patients into gnotobiotic mice that also received injection of murine pancreatic tumor cells revealed the formation of smaller tumors after chemotherapy treatment in mice harboring microbiota from R patients. These effects were found to be mediated by the circulating microbiota-derived tryptophan metabolite 3-IAA, which is significantly enriched in R versus NR patients. Moreover, enhancing dietary concentrations of tryptophan for a short period of time, which led to increased 3-IAA in R-microbiota-colonized mice, reduced tumor weight after chemotherapy. In addition, oral supplementation of 3-IAA turned NR-microbiota-colonized mice into chemotherapy responders. Mechanistically, 3-IAA is oxidized by neutrophil-derived myeloperoxidase after chemotherapy, which induces reactive oxygen species (ROS) by downregulating the ROS-degrading enzymes glutathione peroxidase 3 and 7. Reduced autophagy and cell proliferation were observed, and increasing autophagy could, in turn, increase the sensitivity of cells to chemotherapy, suggesting that autophagy is an essential downstream mechanism behind the synergy of 3-IAA and chemotherapy treatment. Further investigation into the therapeutic potential of 3-IAA revealed that cotreatment of 3-IAA with FIRINOX and gemcitabine/nab-paclitaxel, two main regimens used in PDAC, increased response as compared to either treatment alone. FIRINOX and 3-IAA cotreatment also demonstrated efficacy in colon and lung tumor models, supporting the potential role of 3-IAA in cancer treatment. Finally, in two independent patient cohorts, serum 3-IAA levels were found to correlate with progression-free and overall survival. In summary, this study reveals that the microbiota-derived metabolite 3-IAA aids in mediating chemotherapy response in PDAC and suggests that raising 3-IAA in serum could improve clinical outcomes in this disease.

Tintelnot J, Xu Y, Lesker TR, Schönlein M, Konczalla L, Giannou AD, et al. Microbiota-derived 3-IAA influences chemotherapy efficacy in pancreatic cancer. Nature 2023 Feb 22 [Epub ahead of print].

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