Sunday, November 5, 2017

Hidden arm against tumors: microbiota-enabled checkpoint immunotherapy

This week Science published two studies showing how diverse microbiota directly contributes to efficacy of PD-1 checkpoint immunotherapy in several tumors.

First, we need to mention that senior authors from both papers disclosed associations with for-profit pharma/biotech companies (as cofounders, stockholders, paid consultants or advisory board members). Such associations could, in general, be seen as problematic if one promotes therapy lacking particularities.     

Second, data presented do not advance our understanding how microbiota contributes to the effectiveness of checkpoint immunotherapy. The sole conclusion from both papers is that the more diverse cancer patient's microbiota the more benefit it provides during PD-1 immunotherapy. However, when it comes to narrow down beneficial correlation to particular species we find that one paper reported enrichment of Akkermansia muciniphila while other paper reported enrichment of Faecalibacterium and Clostridiales in Responders (as opposed to Non-Responders).

We still don't know much about the role of microbiota in cancer immunotherapy. I think real advance will come when we define how antigens derived from specific microbiota contribute to anti-cancer immunotherapy either by amplifying existing cross-reactive effector T cells or Foxp3+ Tregs. 

posted by David Usharauli





Wednesday, October 25, 2017

Molecular mimicry to gut microbiota antigen protects against colitis but induces diabetes

Current issue of journal Cell has one very interesting but at the same time confusing research paper. In it, the authors proposed that
(a) diabetes susceptible mice strain, NOD, harbor CD8 T cells specific for microbiota antigen that cross-react with β cell antigen, IGRP, and
(b) such molecular mimicry prevents colitis but at the same time could induce diabetes.

First, the authors showed that MHC I alelle expressed in NOD mice (H2Kd) could bind IGRP206-214 homologue derived from integrase family expressed by some gut Bacteroides species (BacIYL36–44). 



At high dosage, such binding was functional in stimulating high affinity IGRP206-214-specific T cells (17.4+ CD8 T cells).



Human T cells from PBMCs could apparently respond to it as well (though it is strange that it generated better stimulation index than Tetanus toxoid).



Then, the authors did the following experiment. They exposed IGRP-/- 17.4+ TCR transgenic mice to chemical irritant (DSS) and observed that high affinity IGRP206-214-specific T cells, 17.4+ CD8 T cells, but not low affinity ones (17.6+), could protect against colitis (I assume that they used IGRP-/-mice to avoid diabetes development).



It appears that colitis protection depended on perforin expression by 17.4+ T cells. The authors speculated that 17.4+ CD8 T cells prevented colitis by eliminating dendritic cells laden with microbiota-derived antigen (BacIYL36–44).



As a confirmation, the authors showed that germ-free TCR Tg NOD mice colonized with Bacteroides species expressing BacIYL36–44 were protected against colitis.



Colitis protection was observed even in classical, adoptive naive CD4+ T cell transfer colitis model.



Interestingly, however, transfer of T cells from pre-diabetic NOD mice into germ-free NOD.scid mice colonized with Bacteroides species expressing BacIYL36–44 did not accelerate diabetes development (here I assume DSS is required to accelerate T cells priming against IGRP by creating dysbiosis).



In summary, this study suggests the following scenario: diabetes-inducing CD8+ T cells cross-react with gut microbiota-derived antigen. When such microbiota-derived antigens become visible to T cells (during dysbiosis?) CD8+ T cells migrate to gut and eliminate dendritic cells laden with cross-reactive antigens. By eliminating DCs, other T cells are not able to induce inflammation in the gut, thus no colitis. However, the same beneficial CD8+ T cells later migrate to β cells, recognize similar looking antigen, IGRP, and mediate its destruction and diabetes.

Does such circuit makes any evolutionary sense? 

Update: Interestingly, other research group previously detected different set of gut microbiota antigens cross-reactive to IGRP206-214. They used TCR NY8.3 transgenic NOD mice (that recognize the same IGRP epitope) and found that these CD8 T cells cross-reacted with IGRP206–214 homologous peptide, W15944, derived from L. goodfellowii, a member of the phylum Fusobacteria (gram-negative anaerobe), a human and NOD mouse oral commensal. 


posted by David Usharauli   


Thursday, October 12, 2017

Microbiota-generated butyrate works on Aire to amplify Treg numbers

A short but very interesting paper in Journal of Immunology caught my attention this week. In this study the scientists showed that butyrate, a short chain fatty acid derived from fiber fermentation by microbiota acts on GPR41 receptor in the thymus to increase Aire expression and amplify Foxp3+ Treg frequency (of note, compared to WT, GPR41-KO thymus already contains almost 5-fold less Tregs).  




Generally it is believed that microbiota works locally in the gut or other peripheral tissues to either convert naive T cells into Foxp3+ Tregs or expand existing Treg numbers. However no one yet managed to definitely show which pathway is functionally operational in vivo in physiological conditions. This study now could help to further narrow down biological mechanisms responsible for Treg biology. If microbiota-generated butyrate could work on thymus to increase Aire expression that in turn increases level of Thymus-derived Treg generation, then peripheral conversion pathway may play even less relevant role in physiological mechanisms of tolerance.  

The most obvious question after reading this article is why the authors did not test Aire KO mice to verify their conclusions.

posted by David Usharauli