A popular idea for improving PD-1/L1 checkpoint inhibitors focuses on turning “cold” tumors that often evade the immune system into “hot” ones by recruiting more cancer-killing immune cells to the tumor microenvironment.
Now, scientists at University Hospital Zurich showed that immune signaling molecule IL-2 might hold the key to supporting immuno-oncology agents by engaging with dendritic cells, which function as the messengers of the immune system by presenting antigens to T cells.
Treatment with a recombinant IL-2 in mice with melanoma led to an increased number of dendritic cells, which then sensitized cold tumors to be more responsive to checkpoint blockade, according to a new study published in Science Translational Medicine. The researchers suggested that IL-2 treatment might work in synergy with immune checkpoint inhibitors to improve outcomes in patients.
Previous studies have already linked tumor-infiltrating dendritic cells to improved effectiveness of anti-PD-1 immunotherapy. However, scientists don’t fully understand what drives these cells to accumulate in tumors.
IL-2 has been found to stimulate different types of immune cells, including T cells and natural killers, but it was not known to affect dendritic cells. So it was a surprise to the University Hospital Zurich researchers when they observed a major increase in dendritic cell counts in the spleen and lymph nodes of mice after the animals were injected with a recombinant IL-2. The team also found a similar uptick of dendritic cells in lupus patients in a clinical trial who were treated with Proleukin—a human IL-2 formerly owned by Novartis.
After further analysis, the team found that IL-2 boosted the expansion of mature dendritic cells and accelerated the differentiation of dendritic cell precursor by stimulating T cells and lymphoid cells to produce other immune molecules—such as TNF—that can activate dendritic cells.
Based on these findings, the team hypothesized that IL-2 might also facilitate the immune system’s anti-tumor responses. In a mouse model of melanoma, IL-2 treatment increased the number of dendritic cells traveling to cold tumors—which were unresponsive to solo anti-PD-1 antibody treatment—and slowed their growth, the scientists reported.
The researchers also analyzed data from The Cancer Genome Atlas and found that melanoma patients who displayed more IL-2 activity lived longer than those that didn’t.
Proleukin is already being used to treat kidney cancer and melanoma, but its use is limited due to toxicities. A team at the University of Washington recently designed a new protein that resembled IL-2 but spared its dangerous side effects by avoiding the binding to IL-2 receptor alpha.
Other research teams have turned to the interleukin family for help in making tumors susceptible to immunotherapy. A group at Yale University recently pinpointed a modified form of IL-18 that can avoid a decoy receptor expressed in the tumor microenvironment so that it can stimulate durable anti-tumor immune responses.
By showing that IL-2 promoted activation and expansion of tumor-infiltrating dendritic cells, which improves antigen presentation and T cell activation, the University Hospital Zurich researchers argued that IL-2 could play a role in cancer treatment.
“Our findings support the investigation of potential combinatorial approaches in which IL-2 treatment could render poorly immunogenic cancers amenable to treatment with immune checkpoint inhibitors,” the researchers wrote in the study.