Gene therapy reprograms the tumor microenvironment

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The tumor builds around itself a "wall" of immunosuppressive cells or physical and chemical factors that seal off or weaken immune cells. Researchers managed to “hack” and reprogram the tumor microenvironment (TME) using a special “Trojan Horse”. A gene making IFNα was inserted in a cell population within the tumor, imposing an immunostimulatory program to the TME.

The tumor is like a fortress surrounded by walls and ditches, with fierce beasts guarding: immune cells have to overcome many obstacles before they reach and destroy it. Immunotherapy gives them a little help, by targeting immune checkpoints or arming T cells with potent receptors against the tumor. Unfortunately, sometimes the tumor-mediated immunosuppression in the TME gives us a hard time and makes our efforts vain.

If you cannot beat your enemy, try to make you friends: can we make the TME a little more supportive?  

Researchers used gene therapy to place “undercover agents” in the TME and dramatically change its appearance. Gene therapy consists in the insertion of genetic material into a patient’s cells as a strategy to treat diseases. They engineered hematopoietic stem cells (HSC) with a gene making IFNα, a chemical messenger of the immune system; then, they injected such genetically modified cells into mice with leukaemia, where they differentiated into tumor infiltrating macrophages.

Why macrophages?

Macrophages are double-faced cells: they are the first line of defence against pathogens and sustain the activity of other cell populations. Nonetheless, some of them do more harm than good: tumor associated macrophages are an important component of the TME and correlate with a bad prognosis, due to their immunosuppressive properties. If we want to turn the tables in the TME, they are the perfect cell population to start from, as they influence differently other cell types depending their phenotype.

The IFNα transgene is the optimal recipe to turn “bad” macrophages into “good” ones: it is in fact associated with activation, expansion and persistence of tumor specific T cells, the main responsible for tumor destruction. Once delivered by genetically engineered macrophages in a leukaemia mouse model, IFNα reprograms the immunosuppressive TME towards immune activation and effective T cell responses against the tumor.

This strategy can be successfully combined with existing immunotherapies like immune checkpoint inhibitors or CAR-T. It has also the advantage that it does not require the previous identification of tumor antigens, but it activates T cells against multiple tumor associated antigens at a time.

Vitares scientists have a long expertise in gene therapy and immunotherapy. Maybe it is time to combine them into a more efficient strategy. Exploiting combination therapies is the new exciting direction of oncoimmunology and we are ready to take on the challenge!

Erika Salvatori

Reference:

Escobar. G., et al. (2018). Interferon gene therapy reprograms the leukemia microenvironment inducing protective immunity to multiple tumor antigens. Nature Communication 9, 2896.

tumor, gene terapy, tumorimmune system

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