Immunogenic cell death (ICD) represents a unique form of cell death that is capable of provoking an adaptive immune response against dead-cell-associated antigens for immunocompetent hosts. It has been widely recognized that optimal treatments for cancer should not only kill malignant cells but also provoke patient’s own antitumor immune response. Therefore, inducing malignant cells immunogenicity death could provide an important means of cancer therapy. The crux of treatment is immunogenicity of dying cells, which relies on a combination of antigenicity and adjuvanticity. Mutated antigens exposed from dead malignant cells can initiate an adaptive immune response when these dying cells emit adjuvant signals during the processes of cellular stress and death. As the consequence of cellular stress and death, DAMPs (damage-associated molecular patterns), such as ATP, HMGB1, can operate as natural adjuvants to activate PRRs (pattern recognition receptors) signaling to provide the ideal precondition for the initiation of antigen-specific immune responses. Under the selection pressure of immune system, however, both pathogens and malignant cells have evolved limited adjuvanticity and therefore can escape from immune surveillance. During the oncogenesis, malignant cells prefer adopting a pattern of death with no DAMPs released, such as apoptosis, to limit adjuvanticity to escape from immune surveillance. Thus, releasing DAMPs from dying malignant cells is crucial for eliciting a robust antitumor immunity.
Scientists from University of the Chinese Academy of Sciences attempt to propose a new form of cell death, poroptosis, which directly depends on cell membrane nanopores regardless of the upstream signaling of cell death. Poroptosis of malignant cells is sufficient to independently cause immunogenic cell death and trigger antitumor immune response. It has been reported that peptides whose amino acid sequence derived from p53 protein, could permeate cell membrane and even form membrane pores on tumor cells We have identified a peptide (pM1) derived from the fragments of p53-MDM2 binding domain of p53 protein that directly forms irreparable nanopores on the cell membrane of tumor cells, leading to intracellular LDH sustained release, and ultimately, ICD. The pM1-induced cell death was characterized by the sustained release of intracellular LDH, which is distinct from other well-characterized types of cell death induced by FT and detergents that leads to the burst release of intracellular LDH. Our results suggest that the manipulation of poroptosis may be exploited to controllably destroy tumor cells and to modulate immune responses.
They designed and screened one peptide, named pM1; it exhibited a broad-spectrum antitumor activity. We found that pM1-induced necrosis of cancer cells in this study was due to direct disruption of cell membrane rather than depending on p53 signal pathway.They conjugated a palmitic acid with pM1 at its amino terminus, renamed as it as ppM1.They found that both pM1 and ppM1 are capable of causing the loss of membrane integrity, which in turn leads to tumor cell death.They found that ppM1 can rapidly aggregate on plasma membrane and form about 4 nm of nanopores, and these membrane pores can induce ICD on tumor cells and activate antitumor immune response.
They tested the immunogenic properties of ppM1-killed tumor cells in vitro by detecting the maturation status of bone-marrow-derived murine dendritic cells (BMDCs) after co-culturing with necrotic cells induced by ppM1 or freezing-thawing (F/T represents one extremely physiochemical stress that mediates membrane crack to induce accidental cell death) overnight. We found that the ppM1-treated cells significantly stimulated the expression of co-stimulatory molecules CD40, CD80, and CD86 , indicating the maturation of BMDCs.
Their study reveals that ppM1 peptide is capable of forming irreparable transmembrane pores on tumor cell membrane, leading to ICD which we name poroptosis. Poroptosis is directly dependent on cell membrane nanopores regardless of the upstream signaling of cell death. ppM1-induced poroptosis was characterized by the sustained release of intracellular LDH. This unique feature is distinct from other well-characterized types of acute necrosis induced by freezing-thawing (F/T) and detergents, which leads to the burst release of intracellular LDH. Our results suggested that steady transmembrane-nanopore-mediated subacute cell death played a vital role in subsequent activated immunity that transforms to an antitumor immune microenvironment. Selectively generating poroptosis in cancer cell could be a promise strategy for cancer therapy.
Sherry
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