Researchers at the Salk Institute have identified a cellular pathway through which prolonged interferon exposure triggers mitochondrial dysfunction.
A new cellular pathway has been discovered by researchers at the Salk Institute that may explain how interferons, proteins that normally help the immune system fight cancer, can eventually promote tumour growth and contribute to resistance to immunotherapy.
The study links prolonged exposure to interferon II with mitochondrial dysfunction and the production of a molecule called prostaglandin E2 (PGE2), which suppresses anti-tumour immune responses.
Why interferons, which are initially anti-cancer, can become pro-cancer has been a big question in the field. Our study reveals a major reason for why interferons transition from ‘good’ to ‘bad,’ as well as how we can prevent this switch for therapeutic advantage moving forward.”
Gerald Shadel, Professor and holder of the Audrey Geisel Chair in Biomedical Science at Salk.
From anti-cancer response to tumour growth
Interferons are pro-inflammatory signalling proteins that help recruit immune cells such as T cells and B cells to attack cancer cells. However, the researchers found that prolonged exposure to interferon II can have the opposite effect.
Melanoma cells were exposed to interferon I or interferon II for either short or prolonged periods. While acute exposure produced little detectable effect on mitochondria, chronic exposure altered their energy-producing function.
When the researchers transferred the melanoma cells into mice, chronic interferon II exposure unexpectedly increased tumour growth.
The team then investigated the mechanism behind the effect. They found that interferon II causes mitochondrial RNA (mtRNA) to escape from mitochondria into the rest of the cell. The cell interprets this genetic material as a threat, triggering production of interferon I.
Interferons I and II subsequently increase levels of cyclooxygenase 2, an enzyme that promotes production of the bioactive lipid PGE2. The molecule can suppress immune activity within the tumour, helping cancer cells evade the immune response.
Targeting immunotherapy resistance
The researchers next examined whether this pathway could help explain resistance to anti-PD-1 immunotherapies, which are widely used to treat cancer.
“Chronic interferon exposure is a major factor in immunotherapy resistance,” says first author Melissa Johnson, a graduate student researcher in Shadel’s lab. “We wondered whether cancer cells that have become resistant to anti-PD1 therapy were upregulating the immunosuppressive mitochondria-centered pathway we identified, and whether that pathway is a viable target for combating immunotherapy resistance.”
To test the possibility, the researchers prevented melanoma cells in mice from producing PGE2. Removing the signal restored the immune system’s ability to recognise and attack the cancer cells.
The intervention also reversed resistance to anti-PD-1 treatment. In nine of 10 mice, tumours completely regressed and did not return despite having previously resisted immunotherapy.
Source: Salk Institute
Representative images showing mitochondrial RNA (mtRNA) transcripts (red) present outside of the confines of mitochondria (cyan) in a melanoma cell following chronic interferon II exposure. Arrows point to specific examples of mtRNA outside the mitochondria.
Potential route to future treatments
The findings provide a potential therapeutic strategy for overcoming immunotherapy resistance, although the work remains at the preclinical stage and further research will be needed before the approach can be evaluated in people.
Our study enriches our understanding of how the immune system attacks cancer cells but can also be stymied by other factors in the tumor environment, and also conveys the importance of integrating mitochondrial signaling functions into cancer studies.”
Gerald Shadel, Professor and holder of the Audrey Geisel Chair in Biomedical Science at Salk
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