During trogocytosis, immune cells acquire parts of the membrane of cells they interact with. First characterized in aβ-T cells, it later became clear that virtually all immune cells perform trogocytosis. This intercellular transfer of membranes results in the acquisition of proteins that would otherwise not be endogenously expressed by the cell performing trogocytosis, as in the case of Natural Killer (NK) cells that acquire viral proteins from infected cells or cancer antigens from tumor cells. Proteins transferred via trogocytosis are functional and influence the response of the accepting cell. The pathophysiological relevance of trogocytosis is underscored by the high extent that immune cells perform it in the context of infections, autoimmune diseases, and cancer.
NK cells are important mediators of the response against intracellular pathogens and tumors and have been among the first immune cells shown to perform trogocytosis. Trogocytosis has been reported to contribute to the negative regulation of NK cell responses in different contexts. For example, acquisition of m157 or NKG2D ligands not only results in sustained and unproductive cross-linking of activating receptors leading to NK cell anergy but also promotes NK fratricide. On the other hand, acquisition of major histocompatibility complex (MHC) molecules from target cells engaged Ly49 receptors in cis, sustaining inhibitory signaling that dampened NK cell activation. Recently, CD9 was shown to be trogocytosed by NK cells from ovarian cancer cells, resulting in reduced killing capacity. Last, trogocytosis of HLA-G (Human Leukocyte Antigen G) from cancer cells resulted in the generation of NK cells with suppressive properties.
Scientists recently reported that NK cells are suppressed by the checkpoint receptor PD-1 and contribute to the therapeutic efficacy of PD-1/L1 blockade in mouse models of cancer. These results, corroborated by others, were at least partially confuted by findings that murine and human NK cells fail to endogenously express Pdcd1 mRNA or PD-1 protein.
In light of these results indicating that PD-1 is found on the surface of NK cells, and considering the high trogocytosis activity of NK cells, they propose that NK cells acquire PD-1 directly from tumor cells. Mechanistic experiments corroborated our hypothesis and revealed that SLAM receptors were important mediators of PD-1 trogocytosis. Functionally, trogocytosed PD-1 suppressed NK cell–mediated cancer immunosurveillance. Last, analysis of NK cells in patients with clonal plasma cell disorders suggests that PD-1 trogocytosis occurs in cancer patients. Together, our data shed light on a new mechanism that regulates NK cell function via acquisition of PD-1 from tumor cells.
Using leukemia mouse models, we found that lymphocytes perform trogocytosis at high rates with tumor cells. While performing trogocytosis, both Natural Killer (NK) and CD8+ T cells acquire the checkpoint receptor PD-1 from leukemia cells. In vitro and in vivo investigation revealed that PD-1 on the surface of NK cells, rather than being endogenously expressed, was derived entirely from leukemia cells in a SLAM receptor–dependent fashion. PD-1 acquired via trogocytosis actively suppressed NK cell antitumor immunity. PD-1 trogocytosis was corroborated in patients with clonal plasma cell disorders, where NK cells that stained for PD-1 also stained for tumor cell markers. Our results, in addition to shedding light on a previously unappreciated mechanism underlying the presence of PD-1 on NK and cytotoxic T cells, reveal the immunoregulatory effect of membrane transfer occurring when immune cells contact tumor cells.
Sherry
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