In their recent publication in Science Advances, postdoctoral fellows Dr. Mohamed Shaad Hasim and Dr. Marie Marotel uncover a role for trogocytosis in tumor-mediated suppression of NK cells. 

 

Immune checkpoint inhibitor (ICI) therapy has been used with considerable success against various types of cancers. These therapies function by inhibiting checkpoint proteins, such as PD-L1 (programmed death ligand 1), which is upregulated on tumor cells and prevents cytotoxic T cell responses and tumor clearance. As checkpoint proteins play a significant role in inhibiting anti-tumor immune responses, ICI has shown remarkable success in clinical trials over the past decade. 

 

The ability of NK cells to distinguish between healthy and malignant cells makes them promising candidates for cancer immunotherapy. It has been shown that some cancers with low MHC expression are responsive to anti-PD-1 therapy, a phenomenon which can be attributed to NK cell-mediated activity. However, since NK cells do not endogenously express PD-1, the mechanism mediating their inhibition by PD-L1 on tumors was previously unclear. In this paper, Dr. Ardolino’s research group confirms that NK cells acquire tumor-derived PD-1 via trogocytosis. Furthermore, anti-PD-1 therapies enhance NK cell anti-tumor responses by inhibiting the immunosuppressive effects of trogocytosed PD-1. 

 

For the first time, the authors show that the presence of PD-1 on NK cells is acquired by trogocytosis of cellular membranes from tumor cells, which leads to a reduction in their killing capacity. Trogocytosis is a process involving the uptake of plasma membrane proteins from target cells following their activation. Previous evidence has shown that CAR-T cell-mediated trogocytosis of tumor cell antigens greatly impairs their therapeutic potential by causing fratricide. Similarly, trogocytosis of tumor derived NKG2D ligands has also been shown to cause NK cell fratricide. Recently, this phenomenon has also been implicated as a potential tumor escape mechanism during CAR-NK cell therapy.

 

In this study, Dr. Hasim & Dr. Marotel show that inhibition of actin polymerization and ATP synthesis in NK cells, which is essential for trogocytosis, prevented PD-1 acquisition from tumor cells. The authors find that trogocytosis is mediated by engagement of SLAM receptors on NK cells and other lymphocytes, which mediated membrane protein transfer. To confirm that trogocytosed PD-1 contributes to NK cell suppression, the authors injected tumor cells expressing or lacking PD-1 into PD-1 knockout mice. PD-1-expressing tumors grew faster that PD-1 deficient tumors suggesting that when PD-1 was present on tumor cells, they were able to suppress NK cells. Notably, they found that PD-1 blockade restricted tumor growth and the effect was abolished when NK cells were depleted. These data indicate that anti PD-1 reduced the outgrowth of tumors by blocking the immunosuppressive effects of PD-1 acquired by NK cells through trogocytosis.  These effects were also confirmed in human NK cells isolated from patients with multiple myeloma, which acquired membrane antigens from tumors in a similar fashion. 

 

            Altogether, this work highlights the important contribution of NK cell responses against tumors during ICI therapy. Coupling the effects of PD-1/PD-L1 blockade and NK cell activation is an important route of investigation for development of cancer immunotherapies.