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.

Figure 1. Schematic representation of CTLA-4 and PD-1 blockade of T cell activation and attenuation.

Molecular interactions and downstream signaling as a result of ligation of CTLA-4 and PD-1 with their corresponding ligands.

Figure 2. Immune checkpoint inhibitor mechanisms and design.

(A) Mechanisms by which T cell activation by CTLA-4 and PD-1 blockade therapy may cause pituitary and pancreatic β cell damage. CTLA-4 is expressed by normal pituitary cells. Following CTLA-4 blockade (i.e., ipilimumab), the classic complement pathway is activated, resulting in severe inflammation (hypophysitis) and destruction of pituitary cells (23). T cell activation by PD-1 blockade (i.e., nivolumab) can cause pancreatic β cell destruction. Interestingly, PD-L1 is specifically upregulated on pancreatic β cells of patients with T1D, and it is induced by both type I and II interferons via IRF1 (74). Several additional mechanisms are thought to contribute to the efficacy of anti–CTLA-4 and anti–PD-1 therapy (right). These include antibody-mediated depletion of Tregs, enhancement of T cell–positive costimulation within the tumor microenvironment, blockade of host-derived PD-L1 signals from nontumor cells in the microenvironment, and blockade of interactions between PD-L1 and B7-1 (2). Some of these additional mechanisms theoretically play a role in the development of specific organ inflammatory toxicities related to anti–CTLA-4 and anti–PD-1 immunotherapy. (B) Therapeutic mAbs targeting CTLA-4, PD-1, or PD-L1. Left: IgG1 is the isotype of the majority of approved mAb immunotherapies, such as anti–CTLA-4 or anti-CD20 (rituximab). This mAb drives potent antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC), engaging both cellular and humoral immune responses. Center: IgG1-induced ADCC can be increased by defucosylation of the glycan sequences (IgG1fut). This modification, obtained using a specific CHO cell line, enhances mAb binding to FcγRIIIa/CD16. The approved anti-CD20 obinutuzumab is engineered with reduced fucose content. Right: IgG4_S228P is an engineered isotype of IgG4 that displays reduced ADCC and ADCP and no CDC. A serine-to-proline substitution at position 228 (S228P) in the hinge region prevents Fab arm exchanges that frequently occur between IgG4 molecules. IgG4_S228P mAbs, such as anti–PD-1 nivolumab, are mainly blocking agents.

Figure 3. Neoantigens and dendritic cell and CD8⁺ T cell activation at the tumor site following checkpoint blockade immunotherapy.

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.