Learning from the microbes: exploiting the microbiome to enforce T cell immunotherapy

Abstract

The opportunities genetic engineering has created in the field of adoptive cellular therapy for cancer are accelerating the development of novel treatment strategies using chimeric antigen receptor (CAR) and T cell receptor (TCR) T cells. The great success in the context of hematologic malignancies has made especially CAR T cell therapy a promising approach capable of achieving long-lasting remission. However, the causalities involved in mediating resistance to treatment or relapse are still barely investigated. Research on T cell exhaustion and dysfunction has drawn attention to host-derived factors that define both the immune and tumor microenvironment (TME) crucially influencing efficacy and toxicity of cellular immunotherapy. The microbiome, as one of the most complex host factors, has become a central topic of investigations due to its ability to impact on health and disease. Recent findings support the hypothesis that commensal bacteria and particularly microbiota-derived metabolites educate and modulate host immunity and TME, thereby contributing to the response to cancer immunotherapy. Hence, the composition of microbial strains as well as their soluble messengers are considered to have predictive value regarding CAR T cell efficacy and toxicity. The diversity of mechanisms underlying both beneficial and detrimental effects of microbiota comprise various epigenetic, metabolic and signaling-related pathways that have the potential to be exploited for the improvement of CAR T cell function. In this review, we will discuss the recent findings in the field of microbiome-cancer interaction, especially with respect to new trajectories that commensal factors can offer to advance cellular immunotherapy.

Keywords: CAR T cell; cancer immune cell therapy; immunology; immunotherapy; microbiome.

Figure 1

Graphical summary of microbiome-medicated mechanisms improving cancer immunotherapy approaches. Microbial composition shapes a responsive TME in several ways. Strains such as B. longum, B. fragilis, B bifidum and designed consortia have been found to improve T cell priming via increase of MHC class I and II molecules on DCs, tumor infiltration and IFN-γ secretion. Prevalence of A. muciniphila was associated with enhanced IL-12 secretion by DCs causing macrophage maturation towards the M1 phenotype. Microbial metabolites are capable of modulating T cells directly by epigenetic-metabolic reprogramming (M. massiliensis-derived pentanoate) or by inducing the IL-12 receptor on CD4 T cells via the inosine-A2AR axis (B. pseudolongum). TMAO triggers pyroptosis in tumor cells and increases CD8 T cell-mediated antitumor immunity (Clostridiales). Further, engineering of bacteria to produce ICI nanobodies or chemokines were reported to reprogram the TME favorably.

Figure 2

Graphical summary of potential implementation strategies that can be used to apply microbiome-derived mechanisms in cancer immunotherapy. An immunotherapy-favoring microbiome modulation could be achieved by either depleting strains using antibiotics or phages with certain selectivity. Alternatively, establishment of beneficial commensals could be enabled by transplantation of a defined consortium or fecal microbiota of responding patients. Similarly, engineered bacteria reprogramming the TME with soluble mediators is a potential avenue. Additionally, the use of microbial metabolites as postbiotic drugs has the potential to boost immunotherapy.