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.

This new paper, published in Nature Immunology showed that tumor suppressor phosphatase PTEN is involved in type I IFN production in response to viral infection.   

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 PTEN^LoxP/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

Mitochondrial DNA abnormality activates cytosolic type I IFN system

Mitochondria is a cell's energy hub. It is of a prokaryotic (simple bacterial) origin. It has its own DNA. However, prokaryotic DNA can activate innate immune system. So, what would happen if our mtDNA undergo misfolding stress?

This is exactly what the new Nature paper tried to uncover. This study led by Gerald Shadel at the Yale School of Medicine, has examined the outcome of mitochondrial DNA (mtDNA) packaging abnormality by studying mouse model heterozygous for mitochondrial transcription factor A (TFAM^-/+), a protein responsible for mtDNA higher-order nucleoid organization.

Gene expression profiling revealed that cells in TFAM^-/+ mice showed enrichment in IFN-stimulated pathway genes.

The authors showed that this type I IFN response was significantly abrogated in cGAS, STING, IRF3 and TBK1 deficient backgrounds indicating that in TFAM^-/+ mice aberrant mtDNA released into cytosol activates cGAS-STING-IRF3 pathway leading to type IFN production.

Additional experiments showed that such heightened type I IFN response in TFAM^-/+ mice reduced viral cellular burden.

Finally, the authors showed that viruses from herpesviridae family could induce mtDNA misfolding (by TFAM depletion via viral-encoded UL12 M185 molecule) and mtDNA dependent type I IFN response in wild type mice, mimicking TFAM^-/+ mice, suggesting physiological function of mtDNA stress response.

In summary, these results highlight how mitochondrial DNA stress could activate innate immune system and cause inflammation (in human disorders such as systemic lupus erythematosus, cancer, multiple sclerosis, etc).

This study provides additional support for recently described immunological function of mtDNA and its detection by cGAS-STING-IRF3-type I IFN pathway. It is of note that many cellular abnormalities analysed from immunological point of view are converging on type I IFN response.

David Usharauli