Gut microbiota and the paradox of cancer immunotherapy

Abstract

It is recently shown that beneficial environmental microbes stimulate integrated immune and neuroendocrine factors throughout the body, consequently modulating regulatory T-lymphocyte phenotypes, maintaining systemic immune balance, and determining the fate of preneoplastic lesions toward regression while sustaining whole body good health. Stimulated by a gut microbiota-centric systemic homeostasis hypothesis, we set out to explore the influence of the gut microbiome to explain the paradoxical roles of regulatory T-lymphocytes in cancer development and growth. This paradigm shift places cancer prevention and treatment into a new broader context of holobiont engineering to cultivate a tumor-suppressive macroenvironment.

Keywords: cancer immunotherapy; inflammation and cancer; probiotic bacteria; regulatory T-cells; tumor macroenvironment.

Figure 1

Gut bacteria–host crosstalk is continuous and reciprocal in the cancer macroenvironment. Beneficial microbes trigger IL-10-mediated GI-tract immune and neuronal networks that lower systemic inflammatory tone and up-regulate hypothalamic–hypophyseal targets, including oxytocin, constituting a gut–systemic immunity-endocrine-axis. In this way, microbiota stimulate CD4⁺ lymphocytes including regulatory T cells (T_REG) that suppress, promote, or have no effect in carcinogenesis depending upon their timing and prior exposure to gut bacterial antigens and presence of interleukin (IL)-10. This places neoplastic development and growth into a new broader context of the holobiont (comprised of the mammalian host plus resident microbes) and the cancer macroenvironment, highlighting microbes that may be engineered for sustained good health.