Study Shows How Cancer Cells Evade Immunotherapy, Help Select Better Treatment Targets

Study Shows How Cancer Cells Evade Immunotherapy, Help Select Better Treatment Targets

Researchers have discovered a novel mechanism by which tumor cells evade adoptive T-cell therapies — immunotherapies that use a patient’s own blood cells — which may help identify novel, more suitable targets for these therapies.

The study, “Preventing tumor escape by targeting a post-proteasomal trimming independent epitope,” published in The Journal of Experimental Medicine, shows that surface proteins whose trimming does not depend on interferon gamma are better targets for adoptive T-cell therapies.

Adoptive T-cell therapy can be highly effective in treating patients with late-stage cancer. This type of immunotherapy relies on the extraction of T-cells from the blood of the cancer patient and re-introducing them in the patient’s bloodstream.

Although this therapy has shown high response rates in clinical trials for some types of cancers, a high percentage of tumors responding to such therapies eventually recurred.

When the T-cells are engineered to recognize tumor cells, they actually recognize one particular protein that is almost exclusively found at the surface of the tumor cells. Some studies have suggested that this escape mechanism was triggered by the loss of that protein in the tumor cells, which impaired the T-cells from recognizing them.

“The tumors are not recognized by the T-cells,” Ana Textor, a post-doc researcher in Prof. Thomas Blankenstein’s lab at the Max Delbrück Center for Molecular Medicine in Berlin and Charité – University Medicine Berlin, the lead author of the study, said in a press release. “We want to find out how to reduce the frequency with which the cancer recurs after treatment.”

In their experiments, the researchers found that some of the cell surface proteins recognized in these T-cell therapies need to be trimmed and transported to the cell surface in an interferon-gamma (IFNy)-dependent manner. When the tumor cells became insensitive to IFNy, they no longer had the target protein at their surface, and the T-cells could not recognize them as foreign and kill them.

Indeed, when the researchers used T-cells designed to recognize one cancer protein that required IFNy and another that did not, only the T-cells targeting the IFNy-independent protein could permanently destroy the tumors. Despite initial tumor regression, the tumor eventually relapsed when the other T-cells were used.

The researchers also found that the IFNy mechanism was particularly dependent on a trimming enzyme called ERAAP. Without IFNy, the ERAAP enzyme is not activated and therefore does not trim the target protein, preventing it from being displayed at the cell surface.

“Epitopes that do not need processing by the enzyme ERAAP are therefore likely to be a better choice for immunotherapy,” the researchers wrote.

2 comments

  1. nicolae says:

    salute and respect your effort
    On tumor cells
    There is the chance that the individual may control efficiently the occurrence and development activity of malign cells.

    The tumor cells and the disturbances caused by them represent a very complex problem with various unknown elements which make difficult the doctors’ efforts and the patients’ expectancies.
    All information held by the human being until now about the tumor cells are insufficient in order to sole efficiently the malign affections. To this effect, we have to enlarge the knowledge horizon by new „key” information and I have not renounced and I have made this with all my passion and power – in the research study named „All about the malign cells and their fighting”. Now, the importance of the new discoveries may have a significant impact on our anti-tumor defense.
    I have not created this work in order to impress somebody. The thing in stake might be even our lives. I wanted that the people be fully aware of the mechanism generating the occurrence and development of malign affections, as well as the main liable agent so that the human being may redirect and adapt its efficient, preventive defense strategy against malignity.
    It is not easy to carry out such a complex scientific research in an inaccessible field, located beyond the knowledge limits and to succeed revealing some unknown biological mechanism of malign cells and vulnerable „key” points of their behavior which might be selectively attacked.
    I am not an English speaker, I have no support and the translation and editing costs are large, especially to support and continue the fundamental applicative scientific activity of tumor cells.
    I am sorry that such new information and solutions cannot reach the audience much more quickly in order to improve, to test them legally and to obtain the copyrights license.
    While most people is waiting, hoping for years to have something new which may heal them, this new information stays hidden within my papers and documents, having no chance to be known and useful. I am looking for a suggestion and help in order to reveal them to the world, to continue the activity and release one of the four books named „Life beyond all” which includes everything about malign cells and their fighting against (400 pag.).
    Thank you for your attention and support.

    Sincerely yours,
    The author of these works
    Nicolae Gheorghe
    E-mail: Ccnt_nicolae@yahoo.com

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