Predictive Biomarkers of Immune Checkpoint Inhibitors-Related Toxicities

Abstract

The emergence and continuous development of immune checkpoint inhibitors (ICIs) therapy brings a revolution in cancer therapy history, but the major hurdle associated with their usage is the concomitant ICIs-related toxicities that present a challenge for oncologists. The toxicities may involve non-specific symptoms of multiple systems as for the unique mechanism of formation, which are not easily distinguishable from traditional toxicities. A few of these adverse events are self-limiting and readily manageable, but others may limit treatment, cause interruption and need to be treated with methylprednisolone or tumor necrosis factor-α (TNF-α) antibody infliximab, and even directly threaten life. Early accurate recognition and adequate management are critical to the patient's prognosis and overall survival (OS). Several biomarkers such as the expression of programmed cell death ligand 1 (PD-L1), tumor mutation burden (TMB), and microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) have been proved to be the predictors for anti-tumor efficacy of ICIs, but there is a gap in clinical needs for effective biomarkers that predict toxicities and help filter out the patients who may benefit most from these costly therapies while avoiding major risks of toxicities. Here, we summarize several types of risk factors correlated with ICIs-related toxicities to provide a reference for oncologists to predict the occurrence of ICIs-related toxicities resulting in a timely process in clinical practice.

Keywords: PD-1; PD-L1; immune checkpoint inhibitor; predictive biomarker; toxicity.

Figure 1

In the tumor microenvironment, PD-1/CTLA-4 molecules on activated T cells are up-regulated and combined to PD-L1/PD-L2 or CD80/CD86 molecules on tumor cells. Consequently, T cell activity is inhibited, and an immunosuppressive microenvironment is formed, which leads to tumor cells escaping the immune surveillance and growing wildly. ICIs restore anti-tumor activity of T cells by targeting and blocking PD-1 or CTLA-4 signaling pathway. Activated T cells kill tumor cells and may attack normal human tissue cells, forming ICIs-related toxicities. PD-1, programmed cell death protein 1; PD-L1/2, programmed cell death ligand 1/2; CTLA-4, cytotoxic T lymphocyte-associated antigen-4; ICIs, immune checkpoint inhibitors; MHC, major histocompatibility complex; TCR, T cell receptor.

Figure 2

Expression of key potential biomarkers from the tumor microenvironment, circulating blood, target organs or clinical factors, predictive for ICIs-related toxicities. The up or down arrows represent the increase or decrease of biomarkers. All these factors are associated with an increased incidence of ICIs-related toxicities. ICIs, immune checkpoint inhibitors; Tregs, regulatory T cells; IL-6/17/2, Interleukin-6/17/2; HLA, human leukocyte antigen; WBC, white blood cells; RLC, relative lymphocytes count; ctDNA, circulating tumor DNA; CTCs, circulating tumor cells; 18F-FDG, 18F-fluorodeoxyglucose; CRP, C-reactive protein; CTLA-4, cytotoxic T lymphocyte-associated antigen-4; pre-existing ADs, pre-existing autoimmune disorders.