Immune mechanisms of toxicity from checkpoint inhibitors

Abstract

Immunotherapy has changed the treatment landscape for cancer over the past decade. Inhibitors of the immune checkpoint proteins cytotoxic T lymphocyte antigen (CTLA)-4, programmed death (PD)-1, and PD ligand 1 (PD-L1) can induce durable remissions in a subset of patients with metastatic disease. However, these treatments can be limited by inflammatory toxicities that can affect any organ system in the body and in some cases can be life threatening. Considerable progress has been made in understanding the drivers of these toxicities as well as effective management strategies. Further research into understanding the molecular and cellular mechanisms that drive toxicity will enable better prediction of toxicity and development of optimized therapies for these toxicities that avoid interfering with antitumor immunity. In this review, we discuss our current understanding of the inflammatory toxicities from immune checkpoint inhibitors (ICIs) and propose optimal treatment strategies for these toxicities.

Keywords: cancer immunotherapy; checkpoint blockade; immune checkpoint inhibitor; immune-related adverse events; inflammatory toxicity.

Figure 1:. Mechanisms of action of CTLA-4 and PD-1/PD-L1 pathways.

A) CTLA-4 binds tightly to the costimulatory ligands CD80 and CD86, preventing them from interacting with the costimulatory receptor CD28 on T cells. On newly stimulated T cells in the lymph node, CTLA-4 can prevent full activation in a cell intrinsic manner. Tregs express high levels of CTLA-4, enabling them to bind to CD80 and CD86 on dendritic cells (DC) and physically remove these ligands from the DC membrane, preventing subsequent activation of T cells by this DC. B) PD-1 expressing T cells that have entered the tumor microenvironment can bind to their cognate peptide-MHC complex on the target tumor cell, but activation is inhibited when PD-1 binds to PD-L1 expressed on the tumor cell. PD-1 delivers a direct inhibitory signal to T cell through activation of SHP-2 phosphatase, which inhibits signaling downstream of the TCR and CD28. IFNg produced by activated T cells increases PD-L1 expression by target cells, acting as a negative feedback loop.

Figure 1:. Mechanisms of action of CTLA-4 and PD-1/PD-L1 pathways.

A) CTLA-4 binds tightly to the costimulatory ligands CD80 and CD86, preventing them from interacting with the costimulatory receptor CD28 on T cells. On newly stimulated T cells in the lymph node, CTLA-4 can prevent full activation in a cell intrinsic manner. Tregs express high levels of CTLA-4, enabling them to bind to CD80 and CD86 on dendritic cells (DC) and physically remove these ligands from the DC membrane, preventing subsequent activation of T cells by this DC. B) PD-1 expressing T cells that have entered the tumor microenvironment can bind to their cognate peptide-MHC complex on the target tumor cell, but activation is inhibited when PD-1 binds to PD-L1 expressed on the tumor cell. PD-1 delivers a direct inhibitory signal to T cell through activation of SHP-2 phosphatase, which inhibits signaling downstream of the TCR and CD28. IFNg produced by activated T cells increases PD-L1 expression by target cells, acting as a negative feedback loop.

Figure 2:

Major sites of toxicity from immune checkpoint inhibitors.

Figure 3:

Potential Antigenic Targets in Immune Related Adverse Events. The barrier organs (gastrointestinal tract and liver, lungs, and skin) contain a large quantity of microbial and environmental antigens. Endocrine organs such as the thyroid and pancreas produce a variety of specialized proteins. The heart, skinand skeletal muscle express tissue-restricted proteins, which in the case of melanocyte antigens may be shared with melanoma.

Figure 4:

Proposed and cellular mechanisms of immune checkpoint inhibitor (ICI) colitis. Resident memory CD8 T cells (Trm) express CTLA-4 and PD-1 and are in a quiescent state in the healthy colon. The colon also contains abundant regulatory T cells (Tregs) which also express CTLA-4. Upon treatment with CTLA-4 or PD-1 inhibitors, CD8+ Trms become activated, proliferate and produce granzyme B (GZMB) and IFNγ potentially in response to recognition of microbial antigens from the microbiome. This response damages the colonic epithelial cells causing changes in permeability, cell death, and ulceration of the mucosa. Tregs also proliferate though the CTLA-4 on their surface is blocked, reducing their suppressive capacity. IFNγ activates myeloid cells such as tissue macrophages that then secrete TNFα that acts in both a paracrine and autocrine fashion. These macrophages also produce additional inflammatory cytokines and chemokines which can recruit additional activated T cells from the blood, including gut homing CD4+ T cells. Potential treatments for ICI colitis include glucocorticoids which have multiple affects including induction of apoptosis in activated T cells, antibodies to TNFα, integrin inhibitors that prevent trafficking of additional T cells from the blood, JAKi that block IFNg signaling, and CTLA-4-Ig (e.g. abatacept) which can both inhibit priming of new T cells in the gut draining lymph nodes and potentially interfere with ongoing interactions between B71/2 and CD28 on activated T cells in the colonic mucosa.