Science1 publisher3 min readPublished
A mitochondrial RNA leak explains how chronic interferon starts helping melanoma tumors grow
In Science, a Salk Institute team reports that melanoma cells held in type II interferon spill double-stranded mitochondrial RNA, setting off a type I response that raises COX2 and PGE2, and those cells grew tumors faster in mice.
The Scientist · Science desk
What happened
- A Salk Institute team with Gerald Shadel as senior author reports in Science a pathway running from chronic type II interferon exposure through mitochondrial RNA to prostaglandin synthesis.
- Those interferon-exposed melanoma cells were then transplanted into mice, and the chronically type II exposed ones grew tumors faster, a result the team describes as unexpected.
- The authors place the immunosuppression at the end of the chain, where the two interferon signals together raise COX2-dependent synthesis of prostaglandin E2.
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Why it matters
- capability With COX2 and PGE2 named at the far end of the chain, a candidate intervention has four ordered steps to aim at downstream of the interferon signal itself.
- constraint The evidence sits in melanoma cell culture and mouse transplants, so the link to immunotherapy resistance in patients remains a hypothesis the paper does not test.
- decision How much weight a drug developer can put on this depends on the loss-of-function result, and the account available stops at the question.
- precedent Because duration and not the mere presence of interferon produced the effect, interferon studies in tumors now have a reason to report how long exposure ran.
The comparison that carries the argument is duration. Melanoma cells received type I or type II interferon, either for a short exposure or a chronic one [3]. Brief exposure did little to the mitochondria; the chronic arm produced measurable changes in mitochondrial energetic function [4].
Then the cells moved. Interferon-exposed melanoma cells went into a mouse model, and the ones carrying a history of chronic type II exposure grew tumors faster, an outcome the researchers had not anticipated [5]. Because the exposure happened in culture before the transplant, the growth difference reflects a state the cells carried into the animal. The interferon signaling itself did not originate from the host.
Each step of the proposed chain is named. Interferons are the first responders that bring in T cells and B cells to kill malignant cells [15]. Type II interferon pushes mitochondrial RNA out of the mitochondria, and the rest of the cell reads that RNA as an invader and mounts a type I interferon response [7]. "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," the authors wrote [6]. Counting from the leak, four ordered steps separate chronic interferon from the immunosuppressive lipid [16]. The two signals then raise COX2-dependent synthesis of prostaglandin E2, which the authors call "an immunosuppressive pathway implicated in cancer progression and chemo-, immuno-, and targeted therapy resistance" [8].
Gerald Shadel's lab reached this from the opposite direction, having first shown that mitochondria set off interferon responses by releasing mitochondrial DNA into the cell [12]. "For this study, we turned our focus around," Shadel said. "Instead of asking how mitochondria affect interferons, we asked how interferons affect mitochondria." [11] He also framed the gap the work is aimed at: "Why interferons, which are initially anti-cancer, can become pro-cancer has been a big question in the field," he said [9], adding that the 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" [10].
The published account does not carry any of the quantities [17]: no group sizes, no tumor measurements, no magnitude for the mitochondrial change or the rise in PGE2. A reader cannot tell whether the mouse effect is large or marginal. The system is melanoma cells and mice.
The test that would move this from ordered mechanism to target is the loss-of-function arm: melanoma cells that cannot synthesize PGE2. Genetic Engineering & Biotechnology News's account puts that question to the reader, then turns to anti-PD1 immunotherapies as among the most widely used, without reporting what happened [14]. The paper's own title asserts the whole chain, from chronic type II interferon through mitochondrial RNA to prostaglandin synthesis [2].
What to watch
- The PGE2-synthesis-deficient melanoma arm: whether those cells lose the growth advantage once transplanted into mice.
- Whether the same ds-mtRNA-to-COX2 chain appears in tumor types other than melanoma, and whether host T cell numbers move as the pathway predicts.
- Whether tumors from patients whose anti-PD1 treatment stopped working carry the mitochondrial RNA leak signature.