Advances and prospects of biomarkers for immune checkpoint inhibitors

Abstract

Immune checkpoint inhibitors (ICIs) activate anti-cancer immunity by blocking T cell checkpoint molecules such as programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). Although ICIs induce some durable responses in various cancer patients, they also have disadvantages, including low response rates, the potential for severe side effects, and high treatment costs. Therefore, selection of patients who can benefit from ICI treatment is critical, and identification of biomarkers is essential to improve the efficiency of ICIs. In this review, we provide updated information on established predictive biomarkers (tumor programmed death-ligand 1 [PD-L1] expression, DNA mismatch repair deficiency, microsatellite instability high, and tumor mutational burden) and potential biomarkers currently under investigation such as tumor-infiltrated and peripheral lymphocytes, gut microbiome, and signaling pathways related to DNA damage and antigen presentation. In particular, this review aims to summarize the current knowledge of biomarkers, discuss issues, and further explore future biomarkers.

Keywords: DNA damage repair defects; PD-L1; antigen presentation; biomarkers; co-inhibitory receptors; deficient mismatch repair; glycosylation; immune checkpoint inhibitors; immunohistochemical staining; microbiome; microsatellite instability high; plasma biomarkers; tumor gene mutation burden; tumor-infiltrated or peripheral T cells.

Graphical abstract

Figure 1

Biomarkers for ICIs (A) The FDA-approved biomarkers for ICIs including PD-L1 expression, TMB, and dMMR/MSH-H. (B) The potential biomarkers that are currently under extensive investigation.

Figure 2

Schematic illustration of recognition domains by the current anti-PD-L1 antibodies for IHC of PD-L1 The recognition sites of PD-L1 by FDA-approved detection antibodies of PD-L1 (left) and the PD-L1 antibodies used for laboratory research (right) are indicated by brackets that are based on published references.^,,, The graphic is not drawn to scale. IgV, immunoglobulin variable; IgC, immunoglobulin constant; TM, transmembrane; IC, intracellular; aa, amino acid.

Figure 3

Various DNA damage response and main DNA damage repair pathways DNA base-base mismatches that are generated by nucleotide misincorporation during DNA synthesis are repaired by mismatch repair (MMR). Pyrimidine dimers, DNA adducts, and DNA intrastrand crosslinks, which are induced by UV light, some chemicals, oxidative damage, etc., will be repaired by nucleotide excision repair (NER). Direct reversal (DR), which mainly repairs alkylated DNA, does not require nucleotide excision, re-synthesis, and ligation. DNA single-strand break (SSB) is the most frequent DNA damage that is induced by various stresses such as oxidative stress and DNA alkylation and mainly repaired by DNA base excision repair (BER). DNA double-strand break (DSB) is induced by radiation, some chemicals, and DNA replication stress caused by DNA interstrand crosslink. The two main mechanisms of DSB repair include non-homologous end joining (NHEJ) and homologous recombination repair (HRR). NHEJ is the relatively simple repair that joins two DNA ends by the DNA end ligation. In contrast, HRR repairs DSB more accurately using donor DNA as a template.

Figure 4

Inhibitory receptors on T cells and their potential key ligands expressed on APC/tumor cells Other inhibitory receptors, such as CTLA-4, LAG-3, TIM-3, and TIGIT, interact with their ligands to deliver negative signals and inhibit T cell function, which may act as a compensatory mechanism of ICI resistance.