Immunotherapy Calls Up Natural Killer Cells in the Fight against Cancer

Cancer immunotherapy frequently goads T cells to fight cancer more zealously, and now it is starting to demand more of natural killer (NK) cells, too. All too often, NK cells find themselves on the sidelines, fooled by tumor cells that shed the stress proteins that would otherwise serve as “kill me” signals. But what if these tumor cells were obliged to keep what NK cells recognize as badges of infamy? To answer this question, scientists based at the Dana-Farber Cancer Institute and Harvard Medical School interfered with the stress-protein-shedding process.

The stress proteins are called MICA and MICB. Although they may invite destruction by activating natural killer group 2D9 (NKG2D) receptors, they are also subject to proteolytic shedding. To prevent the shedding, the Dana-Farber/Harvard team deployed antibodies that were engineered to target the site where MICA and MICB proteins are cleaved. This approach, the scientists found, reduces the spread of melanoma and lung cancer in mice.

Details of this work appeared in the journal Science, in an article entitled “Antibody-Mediated Inhibition of MICA and MICB Shedding Promotes NK Cell–Driven Tumor Immunity.” According to the article, this new cancer immunotherapy approach can prevent the loss of important immunostimulatory ligands by human cancers and reactivate antitumor immunity.

“We rationally designed antibodies targeting the MICA α3 domain, the site of proteolytic shedding, and found that these antibodies prevented loss of cell surface MICA and MICB by human cancer cells,” the article’s authors reported. “These antibodies inhibited tumor growth in multiple fully immunocompetent mouse models and reduced human melanoma metastases in a humanized mouse model. Antitumor immunity was mediated mainly by NK cells through activation of NKG2D and CD16 Fc receptors.”

In mouse models of melanoma and lung cancer, an engineered antibody called mAb 7C6 not only increased the presence of MICA and MICB on cancer cells, it also increased the infiltration of natural killer cells within tumors. In mice with metastatic melanoma that had spread to the lungs, treatment with monoclonal antibody (mAb) 7C6 helped reduce tumor load.

The new approach was discussed in a related Science Perspective (“Natural Killers Join the Fight against Cancer”) contributed by Adelheid Cerwenka, Ph.D., of Heidelberg University and Lewis L. Lanier, Ph.D., of the Parker Institute for Cancer Immunotherapy at University of California, San Francisco. According to these authors, stimulating NK cells to fight tumors could be an effective part of combination therapies.

“Accordingly, it is feasible to combine the MICA-MICB mAb with immune checkpoint inhibitors such as anti–programmed cell death protein 1 (PD-1), anti–PD-1 ligand 1 (PD-L1), or other T cell–based therapies, including the adoptive transfer of engineered T cells to further enhance T cell activation. These combinations would not only enhance both CD8⁺ T cell and NK cell activation against cancer cells but, in addition, broaden the spectrum of tumor cells that can be attacked.”

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