Chronic interferon exposure prompts a switch from anti-tumor activity to immunosuppression

Good news! Cancer is history (soon)!

"Type II interferon (IFN-II) normally activates the immune system to fight cancer. However, prolonged IFN-II exposure can promote an immunosuppressive tumor environment that supports cancer growth, a confounding factor in cancer therapies. Johnson et al. explored why IFN-driven inflammation can be tumor suppressive in certain contexts but tumor promoting in others.

Chronic IFN-II stimulation unveiled secondary protumorigenic type I IFN (IFN-I) signaling that increased production of prostaglandins, bioactive lipids that inhibit anticancer immune responses.

Suppressing prostaglandin synthesis restored the ability of the immune system to attack tumors and reversed resistance to immunotherapy in melanoma cells.

The IFN-II–mediated IFN-I response was instigated by the release of mitochondrial RNA that activated innate immune signaling.

Timely inhibition of IFN-I signaling or blocking mitochondrial RNA release may therefore provide a means to promote antitumor immunity."

"Highlights

• ... researchers identify what flips a molecular “switch” that causes anti-cancer interferon activity to transition into pro-cancer activity, a longstanding mystery in cancer biology
• Chronic interferon activates a mitochondrial signaling pathway that, when turned off, effectively reverses tumor growth and immunotherapy resistance in a mouse model of melanoma
• The study could reveal new therapeutic targets to sustain anti-tumor immune responses

..."

From the abstract:

"Interferons (IFNs) are proinflammatory cytokines that promote immune cell engagement to eliminate malignant cells.

Paradoxically, chronic interferon signaling can also activate anti-inflammatory mechanisms that allow cancer cells to evade the immune system.

In this study, we sought to determine the cellular mechanisms underlying this switch from antitumorigenic to protumorigenic interferon activity.

We show that chronic type II interferon (IFN-II) exposure distinctively induced tumor growth by activating a type I interferon (IFN-I) response mediated by release of double-stranded mitochondrial RNA (ds-mtRNA) into the cytoplasm. This IFN-I signal synergized with IFN-II to enhance tumor growth by increasing immunosuppressive prostaglandin E2 (PGE2) synthesis through increased cyclooxygenase 2 expression.

Elimination of PGE2 synthesis in immunotherapy-resistant melanoma cells restored their responsiveness to anti-PD1 treatment, indicating that this covert mtRNA-IFN-prostaglandin pathway could be a therapeutic target to combat immunotherapy resistance."

In Science Journals | Science

Why does the immune system sometimes help tumors grow? (original news release) "Salk Institute researchers define how chronic interferon exposure prompts a switch from anti-tumor activity to immunosuppression in mice, revealing a key target to sustain anti-tumor immune responses and combat immunotherapy-resistant cancer"

Chronic type II interferon promotes tumor growth through mitochondrial RNA–induced type I interferon and prostaglandin synthesis (no public access)

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.