Oncolytic virus expressing PGE2 inactivating enzyme display enhanced anti-cancer effect

Oncolytic virus therapy is a new method of cancer therapy. Its goal is to selectively target cancer cells sparing healthy cells. However, not many tumors respond to it and so far it has limited application.

So it was interesting to read new study in Cancer Cell that showed that effectiveness of oncolytic virus cancer therapy could be improved by incorporating prostaglandin-inactivating enzyme (hydroxyprostaglandin dehydrogenase 15-(NAD) (HPGD). 

Initially, the authors tested in vivo susceptibility of several cancer cell lines to oncolytic vaccinia strain (WR.TK^-Luc⁺). Some  cancers were less susceptible (Renca, 4T1), some more (LLC, MC38).

Susceptibility to WR.TK^-Luc⁺ therapy was T cell mediated as CD8 T cell depletion could abolish it.

To overcome inhibitory micro-environment within resistant tumors oncolytic virus (OV) expressing prostaglandin-inactivating enzyme was designed. Indeed, modified OV therapy improved cancer protection.

Moreover, when combined with anti-PD1 therapy, modified OV could protect mice from resistant tumor such as Renca tumor, even when applied on established tumor (aspirin had no effect at this stage).

In summary, this study confirms that sustained inactivation of local prostaglandine source could drastically improve anti-cancer effect of OV, especially when combined with checkpoint inhibitors.

David Usharauli

Dying cells release eicosanoid lipid PGE2 to suppress sterile inflammation and immunogenicity

PGE2 is the most abundant eicosanoid lipid in the inflammatory environment and acts via its receptors EP4 and EP2. Earlier this week I wrote about new study that showed the role of PGE2 in suppressing excessive inflammatory response to endogenous microbiota that gained access to internal organs during systemic infection such as sepsis. 

This time I am reviewing another new paper about PGE2 from PNAS wherein the authors showed that PGE2 released during the process of cell death modulates its immunogenicity.  

Initially, the authors showed that supernatants from cells cultures undergoing various forms of cellular death (freeze-thaw, cisplatin, etoposide or ATP + LPS combination) rather than inducing TNF-α from macrophages it could actually suppress macrophage's response to a canonical inflammatory stimulus such as gram-negative bacterial wall-derived endotoxin, LPS.

Since supernatants treated with DNase I, RNase A, proteinase K or trypsin retained its suppressive activity on the LPS induced production of TNF-α, the authors focus on lipids. Indeed, lipid cellular fraction could reproduce inhibitory effect of the necrotic cell supernatant.

Next, they found that PGE2 was highly enriched in these supernatants and could mediate its suppressive effect.

Synthesis of PGE2 is catalyzed by two cyclooxygenase enzymes, COX-1 and COX-2. Pre-treatment of cells with indomethacin, an inhibitor of COX-1 and COX-2 enzymes, reduced suppressive effect of necrotic cell supernatant.

Finally, using CRISPR/Cas9 gene editing technology, the authors constructed COX-2 deficient tumor cell lines and tested their growth pattern in mice. As expected, growth of COX-2 deficient tumor cell  lines were delayed in absence of COX-2 enzyme.

In summary, this study showed that cells undergoing sterile cell death (for example, during excessive tumor growth), release suppressive lipid, PGE2, and this mechanism represents one of the natural anti-inflammatory processes that is hijacked by tumors to evade efficient immune detection. Aspirin's beneficial effect as an anti-cancer therapy could be attributed to its effect on PGE2. 

David Usharauli

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