Potential marker for success of immunotherapy in the treatment of lung
cancer

Date:
July 8, 2021
Source:
Medical University of Vienna
Summary:
Lung cancer has the highest mortality rate of all cancers, and
treatment options are extremely limited, especially for patients
with oncogenic mutations in the KRAS gene. Some patients respond
very well to treatment with immune checkpoint inhibitors while it
is completely ineffective in others. A research group identified
a potential marker for the success of immunotherapy in lung cancer
patients and explained the underlying molecular processes.



FULL STORY ==========================================================================
Lung cancer has the highest mortality rate of all cancers, and treatment options are extremely limited, especially for patients with oncogenic
mutations in the KRAS gene. A great deal of hope was invested in
the licensing of immune checkpoint inhibitors, but the reality is
that some patients respond very well to this treatment while it is
completely ineffective in others. In a paper just published in Science Translational Medicine, a MedUni Vienna research group led by Herwig Moll (Center for Physiology and Pharmacology) identified a potential marker
for the success of immunotherapy in lung cancer patients and explained
the underlying molecular processes.


========================================================================== K-Ras it is a monomeric G protein that plays a key role in the growth
of malignant tumours. KRAS-mutated lung carcinomas frequently occur
in chronically inflamed lungs, particularly in heavy smokers. The
inflammatory processes promote the growth of cancer cells. The research
group has now shown that the expression of the highly anti-inflammatory
protein A20, formed in the body itself, is often very low in these
malignant cells and that there is a direct correlation between a patient's
life expectancy and the expression of this protein. Moll explains: "Both
in humans and in the animal model, the loss of A20 leads to downgraded
immune surveillance of cancer cells. Cancer cells with low levels of
A20 are able to escape detection by the immune system." This results in significantly faster tumour growth.

During the course of this study, which was co-funded by MedUni Vienna's
Cancer Research Initiative and associated with the Comprehensive Cancer
Center Vienna, the research team discovered that it is primarily an
enhanced sensitivity of the cancer cells to the immunomodulatory cytokine interferon gamma that is responsible for this. Moreover, tumour cells
with downregulated A20 responded particularly well to immune checkpoint inhibitors, in the same way as patients suffering from melanoma (skin
cancer) with a similar gene expression structure.

"In A20 we have discovered a previously unknown tumour suppressor in
lung cancer, the loss of which as an immune checkpoint contributes to
the development of this malignant disease," explains co-author Emilio
Casanova from the Institute of Pharmacology. Since patients with low A20 expression have few tumour-fighting immune cells and so, in the advanced
stage, express little of the important immune checkpoint molecule
PD-L1, these patients could be excluded from immunotherapies directed
against PD-L1. Indeed, the strength of expression of this molecule is
currently regarded as an aid for deciding whether or not they should
be treated with immune checkpoint inhibitors. "Based on our results and
the data available from melanoma patients, we are convinced that we have identified a group of lung cancer patients who would really benefit from
this immunotherapy. Exclusion from such treatment would significantly
reduce the survival rate of such patients." In a further study, the researchers want to find out whether it is possible to manipulate the expression of A20 in the cancer cells, in order to intensify the effect
of immunotherapies. "However, smoking is still the most easily avoided
risk factor for lung cancer. We must therefore support laws to protect
the general public from inhaling harmful smoke, while at the same time appealing to people's personal responsibility to refrain from smoking altogether," says Moll. According to the MedUni Vienna experts, it
is nevertheless important to continue to investigate new therapeutic
approaches to improve the quality-of- life and chances of survival of
those affected.

========================================================================== Story Source: Materials provided by Medical_University_of_Vienna. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Kristina Breitenecker, Monika Homolya, Andreea C. Luca, Veronika
Lang,
Christoph Trenk, Georg Petroczi, Julian Mohrherr, Jaqueline
Horvath, Stefan Moritsch, Lisa Haas, Margarita Kurnaeva,
Robert Eferl, Dagmar Stoiber, Richard Moriggl, Martin Bilban,
Anna C. Obenauf, Christiane Ferran, Balazs Dome, Viktoria Laszlo,
Bala'zs Győrffy, Katalin Dezso, Judit Moldvay, Emilio Casanova,
Herwig P. Moll. Down-regulation of A20 promotes immune escape of
lung adenocarcinomas. Science Translational Medicine, 2021; 13
(601): eabc3911 DOI: 10.1126/scitranslmed.abc3911 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/07/210708103644.htm

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