Saturday, January 9, 2016

Tumor suppressor PTEN promotes anti-viral immunity

In recent years new and powerful immunothereutic strategies such as checkpoint inhibitors (anti-CTLA4/anti-PD1) and CAR-T cells entered into clinics. Moreover, just few months ago, another immunotherapeutic strategy, called oncolytic viral therapy, received FDA approval. This latter approach is very interesting. Basic claim is that this "so called" oncolytic viruses selectively infect and target tumor cells. Of course, this is a nonsense. No virus, including modified oncolytic viruses, could selectively infect tumor cells (and sparing healthy cells). However, analysis of the following paper would explain how oncolytic viruses would "prefer" cancer cells.

To understand significance of this finding in oncolytic immunotherapy, we need to remember that PTEN is a classic tumor suppressor (like p53), which is frequently mutated in cancer cells. Here, the authors initially found that PTEN -/- cells were deficient in type I IFN (but not IL-6) production upon viral infection.

PTEN -/- cells could be rescued to produce type I IFN by transfection with WT PTEN, but not phosphatase[activity]-deficient PTEN (though this PTEN anti-viral phosphatase activity was independent of its phosphatase activity for PI(3)K-Akt pathway).

In vivo experiments with tamoxifen-inducible Cre recombinase PTENLoxP/LoxP mice confirmed essential role of PTEN in anti-viral immunity.

These results could explain why tumors maybe selectively "susceptible" for oncolytic virus immunotherapy. If tumor cell lacks PTEN it becomes sensitive to viral infection since it will fail to produce basic defense anti-viral molecules such as type I IFNs. In a sense, a tumorigenic transformation of healthy cells (as a result of PTEN mutation) comes at cost of reduced anti-viral defense that could be exploited by therapy. However, oncolytic viruses are not regular WT viruses either. They are modified for reduced virulence (WT viruses would not get FDA approval, for sure). So, in the end, positive outcome with oncolytic virus therapy is a sum of (1) reduced anti-viral defense of cancer cells, (2) reduced virulence of oncolytic virus, (3) direct viral cytotoxicity of infected cancer cells, and (4) priming of oncolytic virus-specific T cells (and then cancer epitope spreading).

David Usharauli

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