Abstract
Researchers have figured out a way to switch the immunosuppressive phenotype of tumor-associated macrophages to one that's immunostimulatory. By inhibiting PI3Kγ in these macrophages, they significantly suppressed tumor growth in mice; when anti–PD-1 therapy was added to PI3Kγ inhibition, complete and sustained tumor eradication was observed in many cases.
By expressing anti-inflammatory cytokines, tumor-associated macrophages (TAM) can induce a highly immunosuppressive environment that promotes tumor growth and resistance to immune checkpoint inhibition. However, by targeting PI3Kγ in TAMs, scientists from the University of California, San Diego, in La Jolla, have switched this phenotype to a pro-inflammatory one that stimulates cytotoxic T-cell activity.
In analyzing head and neck squamous cell carcinoma (HNSCC) samples from The Cancer Genome Atlas, the researchers saw an improved survival rate among patients whose tumors expressed high levels of pro-inflammatory cytokines: 97% at 3 years, versus 57% for patients without this favorable immune profile. “We then noticed that mice lacking PI3Kγ had a very similar pro-inflammatory profile,” explains Judith Varner, PhD, the study's senior author. These mice mounted a robust macrophage-mediated immune response to pathogens, she adds. “We hypothesized that PI3Kγ might be inhibiting macrophage inflammatory responses in the tumor microenvironment.”
Varner and her team implanted HNSCC, breast, and lung tumors in PI3Kγ-deficient mice, as well as in mice that had been treated with PI3Kγ antagonists. They reported that tumor growth was significantly suppressed in both settings. In a different set of experiments, TAMs with or without PI3Kγ were transferred along with cultured tumor cells into mice. Tumor development was inhibited only in animals given TAMs that lacked PI3Kγ, Varner says.
The researchers began probing the molecular underpinnings of these observations and found that inactivating PI3Kγ in TAMs affected two other proteins: NFκB, which promotes immunostimulatory effects, was activated; meanwhile, C/EBPβ, which is immunosuppressive, was simultaneously inhibited. This in turn restored the recruitment and activation of cytotoxic T cells, otherwise kept in check by PI3Kγ signaling. Varner and her team also found that PI3Kγ inhibition synergized with anti–PD-1 therapy to boost tumor regression still more in mice with HNSCC.
“We saw complete tumor eradication in many cases,” she says, “and when we rechallenged these mice with new tumors, they got rid of them very quickly, which indicates activation of T-cell memory.”
To Michele De Palma, PhD, of École Polytechnique Fédérale de Lausanne in Switzerland, “PI3Kγ is a promising actionable target for relieving macrophage-induced immunosuppression, thereby facilitating the deployment of T-cell–mediated antitumor immunity.” The therapeutic potential of PI3Kγ inhibition should be explored in the context of other anticancer drugs, he adds—”for instance, in enhancing the efficacy of chemotherapy agents that elicit immunosuppressive macrophages as a side effect.”
Small-molecule PI3Kγ inhibitors such as IPI-549 (Infinity Pharmaceuticals) are already undergoing clinical evaluation, Varner notes. “We need to see if combining these drugs with immune checkpoint blockade in patients recapitulates the great synergy observed in mice.” She's also interested in uncovering other ways to stimulate phenotype switching in TAMs, besides inhibiting PI3Kγ.
“Unless we can change the profoundly immunosuppressive environment that TAMs induce and get them to support rather than thwart T-cell activity, checkpoint blockade and other immunotherapies will only be modestly effective,” Varner concludes. –Alissa Poh
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