Tumor cell deaths can benefit tumors. A paradox? Not at all. If, for example, a dying tumor cell undergoes necroptosis, it can release inflammatory factors that can enhance or diminish antitumor immunity. Consequently, the idea of relying on necroptosis, an inflammatory form of cell death, as an alternative or adjunct to apoptosis, a non-inflammatory form of cell death, needs to be pursued with all due caution.
To determine how necroptosis could be induced as a means of fighting cancer, scientists at the H. Lee Moffitt Cancer Center and Research Institute have been studying necroptosis activation, which involves the necroptosis mediators RIPK3 and MLKL. In a new study, the scientists, who were led by Brian Ruffell, PhD, found to their surprise that RIPK3 and MLKL were dispensable for tumor growth in genetic and implantable models of breast or lung cancer. What’s more, the scientists determined that inducing necroptosis within established breast tumors generated a myeloid-suppressive microenvironment that inhibits T-cell function, promotes tumor growth, and reduces survival.
These effects depended on the release of the nuclear alarmin interleukin-1α (IL-1α) by dying cells. So, if IL-1α drives immune suppression and promotes tumor growth, could blocking IL-1α improve necroptosis-inducing cancer treatments?
This question was addressed by Ruffell and colleagues in the journal Cancer Cell, in an article titled, “Interleukin-1α release during necrotic-like cell death generates myeloid-driven immunosuppression that restricts anti-tumor immunity.”
“IL-1α release occurs during chemotherapy and targeting this molecule reduces the immunosuppressive capacity of tumor myeloid cells and promotes CD8+ T-cell recruitment and effector function,” the article’s authors wrote. “Neutralizing IL-1α enhances the efficacy of single agent paclitaxel or combination therapy with PD-1 blockade in preclinical models. Low IL1A levels correlate with positive patient outcome in several solid malignancies, particularly in patients treated with chemotherapy.”
“We thought necroptosis would help the immune system fight cancer, but instead, it seems to make things worse by helping tumors grow,” said Ruffell, who is an associate member in the Immuno-Oncology Program at Moffitt and the senior author of the new paper. “Our study shows that interleukin-1α is key to this process, and by blocking it, we might be able to help the immune system do its job.”
Essentially, cancer cells that respond to chemotherapy release IL-1α, which could explain why some treatments don’t work as well as expected. But as the preclinical findings in the new study suggest, blocking IL-1α could improve the immune response.
“By blocking the actions of IL-1α, we could make current cancer treatments more successful,” Ruffell said. “Additionally, targeting IL-1α can reduce the toxicity associated with chemotherapy, meaning this approach could help patients respond to and better tolerate therapy.”
Researchers also discovered that lower levels of IL-1α are linked to better outcomes, especially in patients treated with chemotherapy. This suggests that IL-1α could be used as a marker to predict how well cancer treatments might work for different patients.
