Microbial mechanisms to improve immune checkpoint blockade responsiveness

Abstract

The human microbiota acts as a diverse source of molecular cues that influence the development and homeostasis of the immune system. Beyond endogenous roles in the human holobiont, host-microbial interactions also alter outcomes for immune-related diseases and treatment regimens. Over the past decade, sequencing analyses of cancer patients have revealed correlations between microbiota composition and the efficacy of cancer immunotherapies such as checkpoint inhibitors. However, very little is known about the exact mechanisms that link specific microbiota with patient responses, limiting our ability to exploit these microbial agents for improved oncology care. Here, we summarize current progress towards a molecular understanding of host-microbial interactions in the context of checkpoint inhibitor immunotherapies. By highlighting the successes of a limited number of studies focused on identifying specific, causal molecules, we underscore how the exploration of specific microbial features such as proteins, enzymes, and metabolites may translate into precise and actionable therapies for personalized patient care in the clinic.

Keywords: Cancer immunotherapy; Checkpoint inhibitor; Gut microbiota; Microbial metabolites.

Fig. 1

Methods to establish and verify correlations between microbiota and immunotherapy response. [A] Bacterial community composition can be measured by operational taxonomic unit (OTU) clustering or amplicon sequence variant (ASV) assignment of 16S rRNA sequencing libraries that reflect the abundance of different bacterial taxa. [B] Avatar mice that are colonized with microbiota from responding or non-responding patients can be used to phenotype tumor growth and immune checkpoint treatment, which may phenocopy drug efficacy in the original fecal microbiota transplant (FMT) sources. [C] Microbiota that elicit specific immune cell types can be rationally selected through iterative in vivo passaging along with correlation analysis between microbiota composition and immune cell levels. Figure created with Biorender.com.

Fig. 2

Molecular mechanisms of microbiota-mediated potentiation of checkpoint blockade. [A] F. prausnitzii and other microbes produce short-chain fatty acids (SCFAs), which stimulate differentiation and expansion of multiple T cell subsets, including regulatory T (Treg), T helper 1 (Th1), T helper 17, cytotoxic T (Tc1), and memory precursor T (Tmp) cells. [B] B. pseudolongum and L. johnsonii synthesize the purine inosine, which engages A_2AR on Th1 cells to elicit activation in an IL-12- and antigen-dependent manner. [C] A. muciniphilia generates cyclic di-AMP, which activates STING⁺ monocytes to activate natural killer (NK) cells that in turn recruit dendritic cells (DCs). [D] Enterococcus species express and secrete the peptidoglycan hydrolase SagA to produce GlcNAc-MDP and other muropeptides, which activates NOD2⁺ myeloid cells and leads to increased CD8⁺ T cell infiltration and activation. [E] E. gallinarum produces flagellin, which activates DCs and increases CD8⁺ T cell infiltration in a TLR5-dependent manner. [F] E. hirae hosts a phage, in which the tape measure protein (TMP) contains an MHC-I-restricted antigen that can activate CD8⁺ T cells to cross-react with PSMB4-overexpressing tumors. Figure created with Biorender.com.