Time to dissect the autoimmune etiology of cancer antibody immunotherapy
Michael Dougan, Massimo Pietropaolo
Michael Dougan, Massimo Pietropaolo
Published January 2, 2020
Citation Information: J Clin Invest. 2020;130(1):51-61. https://doi.org/10.1172/JCI131194.
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Time to dissect the autoimmune etiology of cancer antibody immunotherapy

Abstract

Immunotherapy has transformed the treatment landscape for a wide range of human cancers. Immune checkpoint inhibitors (ICIs), monoclonal antibodies that block the immune-regulatory “checkpoint” receptors CTLA-4, PD-1, or its ligand PD-L1, can produce durable responses in some patients. However, coupled with their success, these treatments commonly evoke a wide range of immune-related adverse events (irAEs) that can affect any organ system and can be treatment-limiting and life-threatening, such as diabetic ketoacidosis, which appears to be more frequent than initially described. The majority of irAEs from checkpoint blockade involve either barrier tissues (e.g., gastrointestinal mucosa or skin) or endocrine organs, although any organ system can be affected. Often, irAEs resemble spontaneous autoimmune diseases, such as inflammatory bowel disease, autoimmune thyroid disease, type 1 diabetes mellitus (T1D), and autoimmune pancreatitis. Yet whether similar molecular or pathologic mechanisms underlie these apparent autoimmune adverse events and classical autoimmune diseases is presently unknown. Interestingly, evidence links HLA alleles associated with high risk for autoimmune disease with ICI-induced T1D and colitis. Understanding the genetic risks and immunologic mechanisms driving ICI-mediated inflammatory toxicities may not only identify therapeutic targets useful for managing irAEs, but may also provide new insights into the pathoetiology and treatment of autoimmune diseases.

Authors

Michael Dougan, Massimo Pietropaolo

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Figure 3

Neoantigens and dendritic cell and CD8+ T cell activation at the tumor site following checkpoint blockade immunotherapy.

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Neoantigens and dendritic cell and CD8+ T cell activation at the tumor s...
CD8+ T cells are the primary effectors of antitumor immune responses, though other immune cell types (i.e., CD4+ T cells) are also involved. Middle: Dendritic cells (DCs) are activated by neoantigens from the tumor. Dead and dying tumor cells release damage-associated molecular patterns (DAMPs; e.g., heat shock proteins, ATP, nucleic acids) that can also activate DCs. Left: The activated DCs travel to lymph nodes, whereby they present MHC class I–bound neoantigens to naive CD8+ T cells. HLA class I genotype can influence cancer response to checkpoint blockade immunotherapy (107). TCRs binding to the MHC class I–bound neoantigen along with B7-CD28 binding results in the activation of CD8+ T cells specific for the neoantigen. Right: Cytotoxic CD8+ T cells traffic to the tumor site following a chemokine signal (e.g., CXCL9/10 secretion binding to CXCR3 on the T cells). At the tumor site, TCR binding to MHC class I–bound neoantigens to tumor cells has two outcomes: First, it induces IFN-γ secretion, which is bound by IFN-γ receptors in nearby tumor and normal cells, leading to upregulation of MHC class I antigen presentation in those cells. In tumor cells, this facilitates further TCR engagement and cytotoxic activity. Concurrently, IFN-γ also induces PD-L1 expression. Second, it leads to T cell activation and tumor killing through Fas/FasL apoptotic signaling, granzyme and perforin secretion, and direct cell membrane lysis.