Expanded cytotoxic natural killer (NK) cells sensitized nonresponsive lung cancer tumors to anti-PD-1 therapy, rescued tumor killing by exhausted tumor infiltrating lymphocytes (TILs), and upregulated PD-L1 expression in vitro, according to findings from a study published in the Journal for ImmunoTherapy of Cancer.

Insufficient tumor expression of PD-L1 and an immunosuppressive tumor microenvironment cause many cancers to not respond to anti-PD-1/PD-L1 blockade. In addition to T cells, NK and B cells are now known to be involved in the response to immune checkpoint blockade.

Data from previous studies have shown that NK cells can be harvested and expanded from patients with cancer, and therefore may be a novel treatment approach. This study aimed to characterize the therapeutic potential of expanded NK cells in advanced-stage lung cancer and determine whether they can restore sensitivity to anti-PD-1 treatment.

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The study evaluated peripheral blood, pleural effusions, and tumor specimens from 16 patients with advanced lung cancer. NK cells were expanded from peripheral blood using the peripheral blood mononuclear cells from healthy donors or from pleural effusion cells or tumors of the patients with lung cancer.

NK cells were successfully expanded with high viability from lung tumors that were either positive or negative for PD-L1 expression. These cells were found to effectively eliminate cells from a lung cancer cell line. In an engrafted mouse model, the expanded NK cells decreased tumor burden.

Expanded NK cells from patient tumors or peripheral blood (and healthy donor peripheral blood) also eliminated the patients’ tumor cells ex vivo.

The expanded NK cells additionally modulated the tumor microenvironment. In an in vitro model seeded with the patients’ tumors, the expanded NK cells activated endogenous TILs and upregulated PD-L1 expression.

To evaluate whether expanded NK cells enhanced the activity of the anti-PD-1 antibody nivolumab, the investigators treated a lung cancer cell line with interferon-γ to induce PD-1 expression and then incubated it with expanded NK cells with or without nivolumab. The addition of nivolumab enhanced NK elimination of the lung cancer cells. This experiment was performed with patient tumor cells that did not express PD-L1.

“Combined treatment of expanded NK cells and PD-1 blockade resulted in robust synergistic tumor destruction of initially nonresponding patient tumors,” the study authors said.

The greatest amount of tumor cell elimination occurred when expanded NK cells and nivolumab were used, followed by expanded NK cells alone. There was no tumor cell elimination when nivolumab was used alone.

The investigators concluded that “expanded NK cells may overcome the critical roadblocks to extending the prodigious benefits of PD-1 blockade therapy to more patients with lung cancer and other tumors types.”


Poznanski SM, Ritchie TM, Fan IY, et al. Expanded human NK cells from lung cancer patients sensitize patients’ PDL1−negative tumors to PD1-blockade therapy. J Immunother Cancer. 2021;9:e001933. doi:10.1136/jitc-2020-001933