Rapid reuptake of granzyme B leads to emperitosis: an apoptotic cell-in-cell death of immune killer cells inside tumor cells

Abstract

A cell-in-cell process refers to the invasion of one living cell into another homotypic or heterotypic cell. Different from non-apoptotic death processes of internalized cells termed entosis or cannibalism, we previously reported an apoptotic cell-in-cell death occurring during heterotypic cell-in-cell formation. In this study, we further demonstrated that the apoptotic cell-in-cell death occurred only in internalized immune killer cells expressing granzyme B (GzmB). Vacuole wrapping around the internalized cells inside the target cells was the common hallmark during the early stage of all cell-in-cell processes, which resulted in the accumulation of reactive oxygen species and subsequent mitochondrial injury of encapsulated killer or non-cytotoxic immune cells. However, internalized killer cells mediated rapid bubbling of the vacuoles with the subsequent degranulation of GzmB inside the vacuole of the target cells and underwent the reuptake of GzmB by killer cells themselves. The confinement of GzmB inside the vacuole surpassed the lysosome-mediated cell death occurring in heterotypic or homotypic entosis processes, resulting in a GzmB-triggered caspase-dependent apoptotic cell-in-cell death of internalized killer cells. On the contrary, internalized killer cells from GzmB-deficient mice underwent a typical non-apoptotic entotic cell-in-cell death similar to that of non-cytotoxic immune cells or tumor cells. Our results thus demonstrated the critical involvement of immune cells with cytotoxic property in apoptotic cell-in-cell death, which we termed as emperitosis taken from emperipolesis and apoptosis. Whereas entosis or cannibalism may serve as a feed-on mechanism to exacerbate and nourish tumor cells, emperitosis of immune killer cells inside tumor cells may serve as an in-cell danger sensation model to prevent the killing of target cells from inside, implying a unique mechanism for tumor cells to escape from immune surveillance.

Cell-in-cell structures are more potent predictors of outcome than senescence or apoptosis in head and neck squamous cell carcinomas

“…As mentioned above, entosis is described a nonapoptotic cell death program in matrix-detached cells initiated by the invasion of one living cell into another [5]. Wang et al report “emperitosis”, an apoptotic cell-in-cell death process that occurs in heterotypic immune killer cells expressing granzyme B inside tumor cells which may serve as an in-cell danger sensation model to prevent the killing of target cells from inside, implying a unique mechanism for tumor cells to escape from immune surveillance [13]. …”

In-cell infection: bringing uninvited guests

“…B cell ingestion in this context resembles "entosis", a mechanism previously found to mediate cell-in-cell structure formation in epithelial cultures and human tumors [7]. Entosis also promotes the uptake of hematopoietic cells into epithelial cells or cancer cells of various types [8,9]. Incredibly, the authors find that entosis-like internalization of latent EBV-infected B cells (Akata) into cultured nasopharyngeal carcinoma cells (CNE-2) leads to the activation of EBV and the transfer of virus to host (CNE-2) cells.…”

Cell-in-cell phenomenon: A New Paradigm in Life Sciences.

“…The pathway of the first two cell-in-cell deaths is lysosome-dependent cell death [6, 7], and the third one, which is elucidated and termed by us, is a typical caspase-dependent cell death [1, 8, 13]. Interestingly, we found that different immune cells may choose their ways to die inside tumor cells.…”