Abstract
Large amounts of dead and dying cells are produced during cancer therapy and allograft rejection. Depending on the death pathway and stimuli involved, dying cells exhibit diverse features, resulting in defined physiological consequences for the host. It is not fully understood how dying and dead cells modulate the immune response of the host. To address this problem, different death stimuli were studied in B16F10 melanoma cells by regulated inducible transgene expression of the pro-apoptotic active forms of caspase-3 (revCasp-3), Bid (tBid), and the Mycobacterium tuberculosis-necrosis inducing toxin (CpnTCTD). The immune outcome elicited for each death stimulus was assessed by evaluating the allograft rejection of melanoma tumors implanted subcutaneously in BALB/c mice immunized with dying cells. Expression of all proteins efficiently killed cells in vitro (>90%) and displayed distinctive morphological and physiological features as assessed by multiparametric flow cytometry analysis. BALB/c mice immunized with allogeneic dying melanoma cells expressing revCasp-3 or CpnTCTD showed strong rejection of the allogeneic challenge. In contrast, mice immunized with cells dying either after expression of tBid or irradiation with UVB did not, suggesting an immunologically silent cell death. Surprisingly, immunogenic cell death induced by expression of revCasp-3 or CpnTCTD correlated with elevated intracellular reactive oxygen species (ROS) levels at the time point of immunization. Conversely, early mitochondrial dysfunction induced by tBid expression or UVB irradiation accounted for the absence of intracellular ROS accumulation at the time point of immunization. Although ROS inhibition in vitro was not sufficient to abrogate the immunogenicity in our allo-immunization model, we suggest that the point of ROS generation and its intracellular accumulation may be an important factor for its role as damage associated molecular pattern in the development of allogeneic responses.
Highlights
The appearance of cell death during disease therapy is a twopronged sword
reactive oxygen species (ROS) inhibition in vitro was not sufficient to abrogate the immunogenicity in our alloimmunization model, we suggest that the point of ROS generation and its intracellular accumulation may be an important factor for its role as damage associated molecular pattern in the development of allogeneic responses
Conventional studies characterizing cell death are based on PS exposure and ion selectivity of the plasma membrane (AxA5 and Propidium iodide (PI) staining) [15,16,17]
Summary
The appearance of cell death during disease therapy is a twopronged sword. On one hand, cell death is desirable during cancer treatment in order to control malignant cell growth in the patient. Excessive cell death should be avoided during transplantation to allow the grafted cells to survive in a foreign host In the latter case, a considerable number of stresses are involved and several kinds of injuries may compromise tissue viability, leading to progressive graft dysfunction and, eventually, to graft loss [1, 2]. Necrosis, autophagy, necroptosis, and other processes have been reported as common cell death mechanisms observed in vivo during therapies. How these types of cell death modulate interactions of the dying and dead cells with the immune system remains elusive.
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