Checkpoint Inhibitors and Induction of Celiac Disease-like Condition

Abstract

Immune checkpoint inhibitors herald a new era in oncological therapy-resistant cancer, thus bringing hope for better outcomes and quality of life for patients. However, as with other medications, they are not without serious side effects over time. Despite this, their advantages outweigh their disadvantages. Understanding the adverse effects will help therapists locate, apprehend, treat, and perhaps diminish them. The major ones are termed immune-related adverse events (irAEs), representing their auto-immunogenic capacity. This narrative review concentrates on the immune checkpoint inhibitors induced celiac disease (CD), highlighting the importance of the costimulatory inhibitors in CD evolvement and suggesting several mechanisms for CD induction. Unraveling those cross-talks and pathways might reveal some new therapeutic strategies.

Keywords: CLTA-4; Ipilimumab; Nivolumab; PD-1; celiac disease; gut toxicity; immune checkpoint inhibitor; immune toxicity.

Figure 1

T cell activation through checkpoint inhibitors. A schematic presentation of anti-PD-1/PD-L1 and anti-CTLA-4 agents in action. (a) APCs, such as dendritic cells, present processed peptides to T cells on MHC molecules. Upon activation, T cell gradually expresses on its membrane the CTLA-4. When it binds to B7-1/2, it initiates co-inhibition pathways that lead to T cell anergy. In peripheral tissues, activated T cell can be de-activated by the binding of PD-1 to PD-L1 or PD-L2. (b) The anti-CTLA-4 and anti-PD-1/PD-L1 monoclonal antibodies block those inhibitory pathways resulting in effective anti-tumor T lymphocyte responses.

Figure 2

Immune checkpoint inhibitors and celiac disease. (A) Gluten is ingested and digested, reaching the gut lumen as gliadin peptides. (B) Gliadins are rich in glutamine and proline, thus are a prime substrate for deamidation and cross-linking by luminal and mucosal transglutaminases, thus, turning those naïve molecules into immunogenic ones. Transglutaminase capacity to deamidate or transamidate, results in increased post-translation modified proteins (PTMP). Luminal digestive peptidases cannot further break down those bonds, hence, inducing gut inflammation, mucus disruption and intestinal epithelial damage. (C) Gluten increases intestinal permeability by binding to epithelial CXCR3 receptors, resulting in zonulin release. Gliadin-transglutaminase transformed peptides can potentially infiltrate through the open junctions or trans-enterocytically into the lamina propria. A breach in the epithelial barrier exposes the highly immunoreactive sub-epithelium to luminal foreign antigens, stimulating the local immune system. (D) In the lamina propria, gliadin-transglutaminase cross-linked complexes induce pro-inflammatory cytokines. Two types of DC are present, sub-epithelial DCs that send protrusions into the lumen and sense the gut microbiota, and the lamina propria DCs that migrate to lymph nodes, where they present antigens and activate T cells. Immune checkpoint inhibitors block co-inhibitory pathways unleashing effector T cells and depleting regulatory T cells. (E) Uncontrolled activation and proliferation of cytotoxic T lymphocytes (CTLs) further aggravate barrier perturbation, secreting IFNγ and TNFα cytokines, leading to severe intestinal damage.