Opioids Modulate Carcinogenesis via the Gut Microbiome: A Potential Role in Cancer Immunotherapy

Abstract

INTRODUCTION: The US is passing through an opioid epidemic. Although opioids are widely used as potent analgesics in cancer and non-cancer settings, their role is complicated by increased dependence and tolerance. Our group has previously shown that opioids modulate the gut microbiome and the microbiome modulates carcinogenesis in preclinical cancer models. Therefore, we aimed to investigate if opioids, per se, modulate carcinogenesis in mice. METHOD(S): C57BL/6J mice were pretreated with opioid agonists and antagonists and their effect on pancreatic cancer and melanoma was investigated in presence or absence of the gut microbiome. In mice given opioid antagonist naltrexone, tumors were immunophenotyped and role of the immune system was studied through knockout mice and by combining it with immunotherapy (Figure). Fecal 16S ribosomal RNA gene sequencing was used to characterize changes in taxa. RESULT(S): Opioid agonists promoted and opioid antagonists reduced cancer burden in mice. This effect was abrogated in mice given oral antibiotics, co-housed mice, or germ-free mice, thereby highlighting the essential role of the microbiome. In addition, the cancer-reducing effect of naltrexone depended on intact adaptive/innate immune signaling as it was abolished in Rag1-/-- mice, Tlr2-/- mice. Tumors treated with naltrexone had decreased infiltration of IL17+ T-cells and naltrexone potentiated the efficacy of PD-1-based immunotherapy. Finally, sequencing results showed that naltrexone acts as a prebiotic and increases abundance of gut Bifidobacterium and Akkermansia. CONCLUSION(S): Opioids modulate carcinogenesis through the microbiome and the immune system. Human association studies and studies investigating role of gut motility in mediating these phenomena are ongoing. (Figure Presented).