Melanoma and microbiota: Current understanding and future directions

Abstract

Over the last decade, the composition of the gut microbiota has been found to correlate with the outcomes of cancer patients treated with immunotherapy. Accumulating evidence points to the various mechanisms by which intestinal bacteria act on distal tumors and how to harness this complex ecosystem to circumvent primary resistance to immune checkpoint inhibitors. Here, we review the state of the microbiota field in the context of melanoma, the recent breakthroughs in defining microbial modes of action, and how to modulate the microbiota to enhance response to cancer immunotherapy. The host-microbe interaction may be deciphered by the use of "omics" technologies, and will guide patient stratification and the development of microbiota-centered interventions. Efforts needed to advance the field and current gaps of knowledge are also discussed.

Figure 1.

Potential mechanisms of the gut microbiota on innate and adaptive immunity Intestinal microbes (center) act through at least three modes of action (on immunity, metabolism, and vascular, epithelial and/or endothelial barriers) involving host-microbe interactions, leading to exposure or secretion of various mediators that reshape the TME directly (after translocation to distal tumors) or indirectly via the intestinal tract. We have listed published mechanisms of action most often observed in preclinical mouse tumor models. The relevance of these mechanisms in human cancer immunotherapy still needs to be ascertained. PV-1, marker of disurpted gut vascular barrier; MAdCAM-1, Mucosal vascular addressin cell adhesion molecule 1; RGMb: repulsive guidance molecule b

Figure 2.

Multi-omic collections for advancing microbiota science in melanoma Diverse specimen types (e.g., tumor, blood, stool, and saliva) are densely and longitudinally collected before, during, and after treatment, followed by multi-omic data generation and analyses. These data are systematically annotated and deposited into secure, shareable databases and serve as the foundation for subsequent in vitro and in vivo studies, which in turn guide applications for novel diagnostics, prognostics, and therapeutics. Eventually, after clinical trials, these tests and interventions provide rationale for patient-specific interventions and stratifications.

Figure 3.

Systematic, multi-scale tumor microbiology Fresh tumor biopsies are serially sectioned with contamination controls (e.g., operating room environment). Gathered tissue sections are then subjected to imaging and sequencing approaches, which are then combined to determine molecular networks, biomarkers, and putative drug targets. In parallel, microbial cultivation is performed using freshly resected tissue specimens, and the resultant isolates can be injected into organoids and/or enteroids to validate mechanistic hypotheses generated from the multi-scale, multi-omic data.

Figure 4.

Microbiota-centered interventions in cancer Accumulating evidence over the last decade has enabled deconvolution of the taxonomic composition of stools from patients with cancer (at least in distinct malignancies), enabling better definitions of gut dysbiosis and identification of patterns associated with resistance to immunotherapy, independent of PD-L1 tumor expression. Coordinated efforts in biobanking and translational research across investigators, centers, and continents will allow expansion of this progress to other malignancies for better stratification of patient cohorts and personalization of microbiota-centered interventions. LBP, liver biotherapeutic product; FMT, fecal microbiota transplant.