Promoting Immune-Mediated Therapy in Breast Cancer
Despite major progress in early diagnosis and treatment, breast cancer (BC) remains the second leading cause of cancer deaths among women in the U.S. A promising new approach to cancer therapy is immune checkpoint inhibitors (ICIs), antibodies that block receptors on immune cells that suppress the adaptive immune response. Although highly promising in melanoma and lung cancer ICIs have not proven to be very effective against BC, perhaps because of the relatively low numbers of tumor infiltrating lymphocytes (TILs) in most of these malignancies. To address this problem, Vanderbilt University Basic Sciences investigator Rebecca Cook and her laboratory tested the hypothesis that activating retinoic acid inducible gene-1 (RIG-1, a pattern recognition receptor that triggers inflammatory signaling in response to viral double-stranded RNA) could lead to increased TIL populations and greater susceptibility to ICIs in BC. To test the hypothesis, the investigators first searched the Cancer Genome Atlas, which revealed that only 1 or 8 out of 817 BCs exhibited deletion of the gene for RIG-1 or suppressed mRNA expression of that gene, respectively. This confirmed RIG-1 to be a functional target in the vast majority of BCs. They next showed that SLR20, a synthetic RIG-1 ligand, triggered increased RIG-1 levels and activation, leading to pro-inflammatory signaling in BC cell lines shown to express RIG-1, but not in one cell line lacking the protein. SLR20 exposure also triggered death by apoptosis in the responsive cell lines by both the extrinsic and pyroptosis pathways.As pyroptosis is an immunogenic form of cell death, the researchers went on to show that SLR20 caused increased expression of major histocompatibility complex-1 proteins as well as synthesis and release of proinflammatory cytokines and chemokines by BC cells. In fact, medium from SLR20-treated BC cells activated an inflammatory response in RAW 264.7 macrophage-like cells. The researchers devised a nanoparticle-based delivery system to administer SLR20 directly to BC tumors in mice. They found that SLR20 treatment led to upregulation of RIG-1 expression and inflammatory signaling in the tumors. SLR20 also reduced the rate of tumor growth and metastasis, at least in part, by suppressing cell division. In addition, treated tumors exhibited an increase in inflammatory leukocyte populations when compared to control tumors. Thus, the investigators found that when they treated BC tumors with both SLR20 and αPD-L1, a well-characterized ILI, they observed greater suppression of growth than when they treated with either agent alone. The findings support the hypothesis that RIG-1 activation in BC cells results in inflammatory signaling that increases TIL populations, thereby augmenting the susceptibility to ILI-based therapy. The work is published in the journal Cancer Research[D. L. Elion, et al. (2018) Cancer Res., published online September 17, DOI: 10.1158/0008-5472.CAN-18-0730].