Abstract
Our conception of programmed cell death has expanded beyond apoptosis to encompass additional forms of cell suicide, including necroptosis and pyroptosis; these cell death modalities are notable for their diverse and emerging roles in engaging the immune system. Concurrently, treatments that activate the immune system to combat cancer have achieved remarkable success in the clinic. These two scientific narratives converge to provide new perspectives on the role of programmed cell death in cancer therapy. This review focuses on our current understanding of the relationship between apoptosis and antitumor immune responses and the emerging evidence that induction of alternate death pathways such as necroptosis could improve therapeutic outcomes.
Subject terms: Tumour heterogeneity, Cancer microenvironment
Facts
Several signaling pathways have been defined for specific forms of cell death, including apoptosis and necroptosis.
Apoptosis is engaged during development and tissue homeostasis, while necroptosis normally is not.
Apoptosis has been implicated in immune suppression and promoting tumor growth.
Necroptosis is engaged during infection and following specific cell stress signals.
Necroptosis is associated with inflammatory cytokine production and priming of adaptive immune responses.
Open questions
How does necroptosis engage inflammation and adaptive immunity, and how does this differ from apoptosis or unprogrammed necrosis?
Can therapies be found that preferentially trigger immunogenic programmed cell death, such as necroptosis, in tumor cells?
What therapies maximize the immunogenicity of apoptosis, a classically nonimmunogenic form of cell death?
Can inflammatory forms of tumor cell death be used as a novel type of prophylactic tumor vaccination for tumors with conserved antigens?
Will maximizing the immunogenicity of tumor cell death synergize with emerging immunotherapies, such as immune checkpoint blockade?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294769/
Comparing the effects of different cell death programs in tumor progression and immunotherapy
Re: Comparing the effects of different cell death programs in tumor progression and immunotherapy
Introduction
Programmed cell death (PCD) is required for normal growth and development, and maintenance of tissue homeostasis; in these contexts, cell death generally occurs via classical apoptosis. Additionally, evolution has selected for alternate forms of PCD not engaged during development but instead occur in response to pathogen exposure or during cellular stress. Such PCD include necroptosis, pyroptosis, ferroptosis and others, though importantly apoptosis can also be triggered by similar stimuli. Distinct forms of PCD are defined by both specific signaling molecules activated downstream of death-inducing stimuli as well as characteristic morphologies of dying cells following initiation of these programs. This is in contrast to unprogrammed lytic necrosis, or cell death due to loss of plasma membrane integrity mediated by physical stress, which releases cellular contents into the extracellular space independent of any signaling cascades. Several reviews have extensively covered the signaling requirements for distinct PCD pathways [1–9].
Although molecular mediators of each PCD pathway have been identified, the field has only recently focused on how the immune system mechanistically differentiates between these death modalities. In particular, the effects of inflammatory or immunogenic PCD on the initiation of antitumor immune responses are just beginning to be defined. This review focuses primarily on apoptosis and necroptosis as (1) they represent two extremes on the PCD spectrum in terms of inflammation, (2) they often directly antagonize each other, and (3) there is a strong body of evidence for their roles in cancer from which to draw. Abbreviated discussion of the signaling pathways for these two forms of PCD are included below and summarized in Fig. 1.
Programmed cell death (PCD) is required for normal growth and development, and maintenance of tissue homeostasis; in these contexts, cell death generally occurs via classical apoptosis. Additionally, evolution has selected for alternate forms of PCD not engaged during development but instead occur in response to pathogen exposure or during cellular stress. Such PCD include necroptosis, pyroptosis, ferroptosis and others, though importantly apoptosis can also be triggered by similar stimuli. Distinct forms of PCD are defined by both specific signaling molecules activated downstream of death-inducing stimuli as well as characteristic morphologies of dying cells following initiation of these programs. This is in contrast to unprogrammed lytic necrosis, or cell death due to loss of plasma membrane integrity mediated by physical stress, which releases cellular contents into the extracellular space independent of any signaling cascades. Several reviews have extensively covered the signaling requirements for distinct PCD pathways [1–9].
Although molecular mediators of each PCD pathway have been identified, the field has only recently focused on how the immune system mechanistically differentiates between these death modalities. In particular, the effects of inflammatory or immunogenic PCD on the initiation of antitumor immune responses are just beginning to be defined. This review focuses primarily on apoptosis and necroptosis as (1) they represent two extremes on the PCD spectrum in terms of inflammation, (2) they often directly antagonize each other, and (3) there is a strong body of evidence for their roles in cancer from which to draw. Abbreviated discussion of the signaling pathways for these two forms of PCD are included below and summarized in Fig. 1.
Debbie