PGE2-IL-22 axis prevents gut microbiota leakage during systemic inflammation

This week Science published interesting study showing cooperation between prostaglandin E2 (PGE2), one of the most abundantly produced prostaglandin, and innate lymphoid cell (ILC3)-produced IL-22 in keeping gut barrier tight during systemic inflammation (e.g. bacteremia, sepsis, and septic shock).

This is very neatly done study. In the initial experiments, the authors showed that pre-treatment of mice with indomethacin (which suppresses PGE2 production) increased their susceptibility to systemic inflammation following endotoxin (LPS) injection.

Interestingly, when mice were also pre-treated with EP4 agonist (PGE2 receptor), it reduced systemic inflammation following LPS injection. 

Moreover, beneficial effect of EP4 agonist on systemic inflammation following LPS injection was mimicked by antibiotic pre-treatment, suggesting the role of gut barrier in protection mediated by PGE2.

Indeed, EP4 agonist pre-treatment prevented bacterial translocation from gut into sterile internal tissues such as liver.

Finally, the authors showed that PGE2-EP4 signaling in group 3 innate lymphoid cells was necessary for IL-22 production that contributed to maintaining gut barrier function during systemic inflammation (of note, EP4 agonist had (a) no effect in IL-22KO mice and it was still active in (b) RAG KO mice that lack adaptive immune system).

In summary, this study provided additional support for innate cell-derived IL-22 as a cytokine necessary for keeping gut tissue in healthy condition.   

David Usharauli

NSAIDs show synergy with anti-PD1 antibody in cancer immunotherapy

Tumor progression from a single cell to a multicellular state can take years and several mutations that allow cancer cells to (1) expand uncontrollably, and (2) adopt natural defense mechanisms against immune surveillance (commonly referred as tolerance). 

Ordinarily, healthy (or healing) tissues defend themselves against excessive immune probing by secreting or expressing inhibitory molecules. Each healthy tissue will have its own suitable natural defense(s) against excessive immune probing.

There are several known tissue specific inhibitory signals. Many are still unknown. By understanding how healthy tissues communicate tolerogenic signals to immune system we can gain better control over cancer tissue (because cancer tissues are imitating the same tolerogenic state). 

For example, new pepar in prestigious journal Cell showed that blockade of COX1/COX2 enzymes leads to tumor control by adaptive immune system. COX1/COX2 enzymes are the same enzymes the drugs such as aspirin targets to relieve the pain. 

This is very straightforward article. The reason it is in Cell has to due with CRISPR/Cas9 technology the authors has used to develop COX1 or COX1/COX2 double deficient tumor cell lines. The senior author on this paper is Caetano Reis e Sousa, a wellknown name among immunologists. This study was done at the Francis Crick Institute in London which  will be the largest biomedical institution in Europe when completed.

Initially, the authors developed melanoma-prone cell lines (Braf^v600E) deficient for COX enzymes using CRISPR/Cas9 technology.

Next, the authors showed that Braf^v600E melanoma tumor cells deficient for COX1/2 enzymes lack the ability to secrete PGE2 (among other bioactive lipids), a prostaglandin molecule known for its immunomodulating property.

The authors observed that when transplanted COX1/2 DKO melanoma Braf^v600E tumor cells (but not parental cells) were rejected by wild-type, but not by RAG KO hosts, implying the role of adaptive immune system in recognizing tumor cells in absence of PGE2.

Similar results were obtained with melanoma Braf^v600E tumor cells selectively deficient for PGE2 synthase.

Growth of other tumor cell lines (colorectal and breast cancer cells) deficient for COX1/2 enzymes were also controlled by adaptive immune system in wild-type hosts, though less efficiently compared to melanoma cells (the authors do not indicate whether these tumors were ultimately rejected or stayed dormant).

Finally, the authors showed that combination of aspirin (that blocks COX1/2 enzymes) and anti-PD1 antibody could synergize in inhibiting tumor growth (here also it is not clear what term "rejection" means, since tumor growth graph and rejection graph are not identical).

In summary, the data presented in this paper expands our understanding of "natural" defenses of tumor cells against immune probing. Here, tumor growth was controlled by T cells and it could generate memory response to secondary tumor transplantation.

One weakness of this study is the tumor transplantation model itself. The authors did not study already established tumors but rather than they followed the tumor growth or implemented therapy immediately after transplantation. This approach seems to lack a clinical relevance for human cancers where patients are frequently first seen with already established tumors (sometimes quite in advance stages).

David Usharauli