Immune checkpoint blockade induces gut microbiota translocation thataugments extraintestinal anti-tumor immunity

Choi, Y. et al. (BioRxiv) doi: 10.1101/2022.01.26.477865

Keywords

  • Microbiome

  • Cancer

  • Immune checkpoint therapy

 

Main Findings

While the microbiota’s role in cancer immunotherapy has gained increasing appreciation, the mechanisms by which the microbiota influences responses to immune checkpoint blockade remain elusive. Microbiota translocation into secondary lymphoid organs has been observed in inflammatory diseases, infectious diseases, and cyclophosphamide-mediated anti-tumor responses. In this preprint, Choi et al. demonstrated that immune checkpoint therapy (ICT) induced bacterial translocation during an effective anti-tumor response. Utilizing a murine model of subcutaneously implanted B16-F10 melanoma cells, the authors collected stool and various organs throughout ICT treatment course. Choi et al. found that after initiation of ICT, there was translocation of bacteria to mesenteric lymph node, tumor draining lymph node, spleen, and tumor. Culturing and sequencing revealed that the most abundantly translocated bacteria were Enterococcus sp., Lactobacillus johnsonii and Enterobacteriacea. Choi et al. then demonstrated that these bacterial species could induce distinct immune responses to facilitate anti-cancer immunity. For example, the authors showed thatCD8+T cells primed with dendritic cells pulsed with E. faecalis, L. johnsonii, and E coli induced significantly higher CD69+ expression and IFN-production in CD8+T cells. The authors observed that ICT-induced bacterial translocation into mesenteric lymph nodes(MLNs)occurred in wild-type mice but not in dendritic cell-depleted mice. Through quantification of bacterial load in DCs by quantitative-PCR and 16Ssequencing, Choi et al. also show that DCs facilitate ICT-induced gut microbiota translocation into secondary lymphoid organs.

By surgically removing MLNs, the authors demonstrated that MLNs serve as important mediators in the gut microbiota-dependent extra-intestinal anti-tumor immune effects observed with ICT. They hypothesized that MLN may serve as a gateway by which gut microbiota-induced immune signals are delivered to extra intestinal sites.

Lastly, Choi et al. showed that antibiotic treatment decreased gut microbiota translocation into MLN, decreased polyfunctional CD8+T cell effector responses, and diminished ICT efficacy.

Overall, this study showed that an optimal anti-tumour immune response by ICT involves bacterial translocation from the gut to extraintestinal sites. Additionally, the translocated bacteria taxa should also be sufficiently immunogenic to elicit an anti-cancer immune response by the innate and adaptive immune system.

Limitations

  • Additional contaminations controls taken at steps including tissue dissection, tissue processing, bacterial culturing, DNA extraction, and sequencing would be helpful. This would be insightful to show that results were not affected by possible contamination present on operator hands, molecular reagents, etc.

 

  • In vitro experiments may not be representative of the complexity that occurs in vivo.

 

  • The microbiota studied was a mouse microbiome and may limit the generalizability of these findings to human microbiotas.

 

Significance/Novelty

 

This preprint contributes to the small but growing body of work within the microbiome-immunotherapy space bydescribing how microbiota translocation to distal body sites may play a role in ICT response. This preprint provides evidence to clarify how the microbiota may exert its effects on distal sites, such as the MLN’s role in anti-tumor immunity, and the role of dendritic cells in trafficking bacteria to these extraintestinal sites. Additionally, Choi et al show that in their model, the most abundantly translocated bacteria identified by culturing and sequencing included Enterococcus sp, Lactobacillus johnsonii, and Enterobacteriaceae.

This preprint also highlighted how the use of antibiotics may attenuate ICT efficacy through decreased gut microbiota translocation to MLN. This would be important to consider when considering antibiotic treatment in patients receiving ICT.

Credit

Reviewed by Joan Shang as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai and the Kennedy Institute of Rheumatology, University of Oxford. You can follow her on Twitter.