Mixed signals impair communications of all sorts—including communications between immune cells struggling to fend off cancer. According to a new study led by scientists at the University of California (UC), Irvine, mixed signals between cytotoxic T cells and immunosuppressive T cells—specifically, CD8+ cells and T regulatory (Treg) cells—can weaken the response to checkpoint immunotherapy. Indeed, the scientists have found that interrupting CD8+-to-Treg signaling before PD-1 immunotherapy “improves control over immunogenic melanoma.”

These findings appeared in Cancer Cell, in an article titled, “Interruption of the intratumor CD8+ T cell:Treg crosstalk improves the efficacy of PD-1 immunotherapy.”

“[We] show that PD-1 blockade increases tumor-Tregs in mouse models of melanoma and metastatic melanoma patients,” the article’s authors wrote. “Mechanistically, Treg accumulation is not caused by Treg-intrinsic inhibition of PD-1 signaling but depends on an indirect effect of activated CD8+ T cells.”

“CD8+ T cells produce IL-2 and colocalize with Tregs in mouse and human melanomas,” the authors explained. “IL-2 upregulates the anti-apoptotic protein ICOS [inducible co-stimulator] on tumor-Tregs, promoting their accumulation.”

According to the scientists, their findings suggest a new strategy that could enhance the therapeutic effectiveness of checkpoint therapy, such as PD-1 blockade, which has become the standard of care for metastatic melanoma. While this treatment is effective in 40% of patients, the other 60% develop resistance, leading to tumor regrowth.

While PD-1 blockade activates a potent antitumor response in CD8+ T cells, it also promotes the accumulation of Tregs, decreasing the immune response against the tumor. The activation of these competing signals—one set combatting the tumor, and the other restraining the immune system—is likely a significant challenge in providing effective cancer treatment.

“Our latest research reveals that CD8+ T cells, activated by PD-1 blockade to target melanoma, also interact with Tregs, which subsequently dampen the immune response against the tumor,” said corresponding author Francesco Marangoni, PhD, assistant professor of physiology and biophysics, UC Irvine. “We analyzed the intricate dynamics of communication between CD8+ T and Tregs, which are analogous to two telephone landlines connected by a cable. If we cut the cable, the CD8+ T cells won’t be able to ‘call’ the Tregs and instruct them to inhibit the immune response to the cancer.”

Team members focused on the mechanism of communication between CD8+ T and Tregs in tumors and identified a pivotal role for ICOS, a molecule that is required for T-cell activation. They found that by neutralizing ICOS and PD-1, CD8+ T cells increased their activity against the tumor but could no longer stimulate Tregs.

“Our work helped identify a reason why some patients treated with checkpoint blockade develop resistance to it,” said Shannon Geels, the study’s first author and a UC Irvine graduate student researcher in the Department of Physiology and Biophysics. “We found that communication between cells can lead to immunotherapy failure and that we can improve efficacy by interrupting specific messages exchanged by immune cells.”

The next phase of this research involves understanding the complex communication network among various cell types in a tumor.

“We do not think there is only one ‘phone cable’ to cut,” Marangoni pointed out. “Our findings provide a promising pathway to increasing our understanding of communication among all cell types within a tumor. This will enable us to identify the messages that block the full potential of CD8+ T cells stimulated by PD-1 blockade so that we can maximize the benefit to patients.”

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