PD-L1 blockade enhances anti-tumor efficacy of NK cells

Abstract

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.

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

“…NK cells, in addition to other immune cell subsets such as Tcells, may also be involved in some of these toxic side effects (165)(166)(167)(168). In addition, though therapies targeting inhibitory checkpoint receptors expressed on NK cells, such as anti-PD-1 and the PD-1 ligand, PD-L1, increase NK cell activity (121,169,170), they may inadvertently cause various dose-dependent immune-related adverse events, such as pneumonitis, colitis, hepatotoxicity, endocrinopathies, and neurological and cardiac toxicities (171).…”

“…Additional strategies may synergize with current mAb therapy/ICI therapy by reducing the NK cell activation threshold. This could be achieved by masking tumor checkpoint ligands [i.e., anti-PD-L1, Avelumab, which can also initiate NK cell ADCC (69,120,169,261,278,279), or the TIGIT ligands CD112/CD155 (105,280,281)], activating NK cells in-situ with cytokine variants, and modulating tumors via bio-chemical modifications or inhibitors, making them more susceptible to NK cell-mediated lysis.…”

Multiscale Agent-Based and Hybrid Modeling of the Tumor Immune Microenvironment

“…T-cell exhaustion is also frequently found in the tumor microenvironment through the PD-L1/PD-1 pathway [20]. PD-1 blockage enhances T-cell and NK (Natural Killer) cell activity in tumors [21,22]. Several immune checkpoint inhibitors are currently being used in treatments of patients with cancer [23,24].…”

Harnessing the immune system after allogeneic stem cell transplant in acute myeloid leukemia

“…The theory is that by blocking immune checkpoints—such as the interaction of cytotoxic T‐lymphocyte‐associated protein‐4 (CTLA‐4) and programmed death‐1 receptors (PD‐1) with their respective ligands—immune checkpoint inhibitors can prevent tumors from evading the donor immune system. There is also evidence that checkpoint blockade may enhance NK cell activity . The major concern with using immune checkpoint inhibitors after allo‐SCT is the increased risk of GVHD.…”