As soon as a cancer cell appears, the immune system jumps into action—and interferons (IFNs) are among the first responders. Interferons are pro-inflammatory cytokines, or signaling proteins, that recruit specialized immune cells, such as like T cells or B cells to destroy the cancer. This is a critical, powerful step in the body’s fight against cancer, but chronic exposure to interferons can turn them from ally to enemy.
A Salk Institute team has now discovered a novel pathway that links chronic interferon II (IFN-II) exposure to mitochondrial dysfunction that ultimately causes immunosuppression. By explaining how interferon II turns from “good” to “bad,” the foundational insights provide a path to future therapies that combat immunotherapy resistance.
“Why interferons, which are initially anti-cancer, can become pro-cancer has been a big question in the field,” says senior author Gerald Shadel, PhD, professor and holder of the Audrey Geisel Chair in Biomedical Science at Salk. “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.”
Shadel is senior and corresponding author of the researchers’ published paper in Science, titled “Chronic type II interferon promotes tumor growth through mitochondrial RNA–induced type I interferon and prostaglandin synthesis.”
Cancer biology and, in turn, cancer treatment have come a long way in the last few decades. Most people recognize this progress in breakthroughs like immunotherapy—a treatment strategy first deployed in 2011 that leverages the body’s own immune cells to fight cancer and revolutionized the treatment landscape. However, progress doesn’t mean all the questions have been answered.
One of those questions is why interferons that recruit the immune system to attack cancer cells can, when they linger too long, start helping the tumor grow rather than shrink. “Interferons (IFNs) are proinflammatory cytokines that promote immune cell engagement to eliminate malignant cells,” the authors wrote. “Paradoxically, chronic interferon signaling can also activate anti-inflammatory mechanisms that allow cancer cells to evade the immune system.”
Shadel’s lab has been studying interferons for a while, and for his team, the context is always mitochondria. The Shadel lab first discovered that mitochondria invoke interferon responses through the release of mitochondrial genetic material (mtDNA) into the rest of the cell. The lab’s research seeks to uncover the ways mitochondrial dysfunction can lead to inflammation, aging, and pathology.
“For this study, we turned our focus around,” Shadel explained. “Instead of asking how mitochondria affect interferons, we asked how interferons affect mitochondria. And cancer is a powerful system to ask this question in, since interferons are so essential to the body’s cancer response.”
To determine how interferons affect mitochondria the team first exposed melanoma cells to interferon I or interferon II for either acute or chronic periods. Little happened to the mitochondria on acute exposure, but chronic exposure led to measurable changes in their energetic function. The researchers then transferred these melanoma cells to a mouse model, finding that chronic interferon II exposure unexpectedly enhanced tumor growth.
The team next worked to decipher the cellular mechanisms behind the enhanced tumor growth. They found interferon II causes mitochondrial genetic material (mtRNA) to leave the mitochondria, where the rest of the cell perceives it as an invader and produces interferon I to respond. “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,” they noted.
Interferons I and II then work together to boost levels of the enzyme cyclooxygenase 2, which increases the synthesis of the bioactive lipid prostaglandin E2 (PGE2). “These IFN-II and IFN-I signals then synergize to up-regulate COX2-dependent PGE2 synthesis, an immunosuppressive pathway implicated in cancer progression and chemo-, immuno-, and targeted therapy resistance,” the team continued.
If prostaglandin E2 is causing immunosuppression, the team asked, what then happens if the melanoma cells are incapable of synthesizing PGE2?
Anti-PD1 immunotherapies are among the most widely used immunotherapies. They work by blocking a signal that cancer cells use to keep immune cells from attacking the tumor. But tumors can also suppress the immune system through other pathways, allowing them to continue growing despite anti-PD1 treatment.
“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.”
The researchers blocked the synthesis of prostaglandin E2 in mouse melanoma cells. They found that eliminating this signal restored the immune system’s ability to see and fight the cancer cells. Blocking prostaglandin E2 also reversed resistance to anti-PD1 immunotherapies. In nine of 10 mice evaluated the tumors completely regressed and didn’t return, even though they were previously resistant to immunotherapy.” 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,” the team concluded.
The findings demonstrate potential for clinical translation in the future, offering a potential way to sustain the immune system’s attack on cancer and hope in cases of immunotherapy resistance. “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,” said Shadel, “and also conveys the importance of integrating mitochondrial signaling functions into cancer studies.”
