Led by Dr. Alicja Copik, scientists at the University of Central Florida College of Medicine have discovered that it might be possible to make cancer immunotherapy work for a larger portion of patients by employing PM21-activated natural killer (PM21-NK) cells .
Anti-PD-1/anti-PD-L1 therapies have shown success in cancer treatment but responses are limited to ~ 15% of patients with lymphocyte infiltrated, PD-L1 positive tumors. Hence, strategies that increase PD-L1 expression and tumor infiltration should make more patients eligible for PD-1/PD-L1 blockade therapy, thus improving overall outcomes. PD-L1 expression on tumors is induced by IFNγ, a cytokine secreted by NK cells. Therefore, we tested if PM21-particle expanded NK cells (PM21-NK cells) induced expression of PD-L1 on tumors and if anti-PD-L1 treatment enhanced NK cell anti-tumor efficacy in an ovarian cancer model. Studies here showed that PM21-NK cells secrete high amounts of IFNγ and that adoptively transferred PM21-NK cells induce PD-L1 expression on SKOV-3 cells in vivo. The induction of PD-L1 expression on SKOV-3 cells coincided with the presence of regulatory T cells (Tregs) in the abdominal cavity and within tumors. In in vitro experiments, anti-PD-L1 treatment had no direct effect on cytotoxicity or cytokine secretion by predominantly PD-1 negative PM21-NK cells in response to PD-L1+ targets. However, significant improvement of NK cell anti-tumor efficacy was observed in vivo when combined with anti-PD-L1. PD-L1 blockade also resulted in increased in vivo NK cell persistence and retention of their cytotoxic phenotype. These results support the use of anti-PD-L1 in combination with NK cell therapy regardless of initial tumor PD-L1 status and indicate that NK cell therapy would likely augment the applicability of anti-PD-L1 treatment.
NK cells, IFNγ, and PD-L1
Interferon gamma (IFNγ), a cytokine secreted by natural killer cells, is known to induce the expression of programmed death-ligand 1 (PD-L1) in certain tumors. PD-L1 protects these tumors, leading to an immunosuppressive tumor environment of regulatory T cells while crippling and killing cytotoxic T cells.
An immunotherapy known as PD-1/PD-L1 blockade works by inhibiting the association of PD-L1 with its receptor protein, programmed cell death protein 1 (PD-1), and has proven to be very successful against certain types of cancer, allowing the immune system to fight back and stopping even metastatic cancers in their tracks. Unfortunately, these therapies only work for relatively small, case-dependent percentages of patients, as in most cases, PD-L1 isn’t sufficiently expressed for PD-1/PD-L1 blockade to be effective.
Dr. Copik and her team wanted to see whether it would be possible to make PD-1/PD-L1 blockade applicable to a larger cohort of patients. They hypothesized that enhancing NK cells with PM21 particles (plasma membrane particles expressing membrane-bound interleukin-21) might induce tumor cells to express sufficient PD-L1 to make PD-1/PD-L1 blockade a viable option.
Indeed, when Dr. Copik’s team tried the modified NK cells in combination with anti-PD-L1/anti-PD-1 drugs in live mice affected by ovarian cancer, they observed that survival rates improved. In the study, PM21-NK cells were found to be highly cytotoxic to ovarian cancer cells and stimulate PD-L1 expression both in vivo and in vitro. With the blockade in place, the immunosuppressive tumor environment was unable to take hold, and the tumors were destroyed.
NK cell therapy doesn’t cause the side effects typical of chemotherapy and radiation, and NK cells can even be safely harvested from other people and implanted in patients, even in case of a less-than-perfect match. Therefore, a combination of PM21-NK cells and PD-1/PD-L1 blockade might be used in human clinical trials—as a matter of fact, Dr. Copik’s method to enhance natural killer cells has been patented and is on its way to be tested in clinical trials against leukemia.
 Oyer, J. L., Gitto, S. B., Altomare, D. A., & Copik, A. J. (2018). PD-L1 blockade enhances anti-tumor efficacy of NK cells. OncoImmunology, 1-11.