Biomarkers for predicting efficacy of PD-1/PD-L1 inhibitors

Abstract

Programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) is a negative modulatory signaling pathway for activation of T cell. It is acknowledged that PD-1/PD-L1 axis plays a crucial role in the progression of tumor by altering status of immune surveillance. As one of the most promising immune therapy strategies, PD-1/PD-L1 inhibitor is a breakthrough for the therapy of some refractory tumors. However, response rate of PD-1/PD-L1 inhibitors in overall patients is unsatisfactory, which limits the application in clinical practice. Therefore, biomarkers which could effectively predict the efficacy of PD-1/PD-L1 inhibitors are crucial for patient selection. Biomarkers reflecting tumor immune microenvironment and tumor cell intrinsic features, such as PD-L1 expression, density of tumor infiltrating lymphocyte (TIL), tumor mutational burden, and mismatch-repair (MMR) deficiency, have been noticed to associate with treatment effect of anti-PD-1/anti-PD-L1 therapy. Furthermore, gut microbiota, circulating biomarkers, and patient previous history have been found as valuable predictors as well. Therefore establishing a comprehensive assessment framework involving multiple biomarkers would be meaningful to interrogate tumor immune landscape and select sensitive patients.

Keywords: Gut microbiota; Microsatellite instability; PD-1/PD-L1 inhibitors; Peripheral biomarker; Predictive biomarkers; Tumor mutational burden.

Fig. 1

The effect of TGF-β signaling pathway in fibroblast on T cell infiltration. Activated TGF-β signaling pathway in peritumoral fibroblast induces the production of collagen fiber. Collagen fiber surrounding tumor limits T cell infiltration into tumor bed

Fig. 2

The role of IFN-γ signaling pathway in adaptive immune resistance and immune surveillance. IFN-γ binds to IFN-γ receptor (IFNGR) on the tumor cell membrane and then activates associated Janus kinase (JAK). Subsequent recruitment and phosphorylation of signal transducers and activators of transcription 1 (STAT1) regulate transcription of Interferon Regulatory Factor-1(IRF-1) in nucleus. IRF-1 promotes PD-L1 expression while interferon-stimulated gene (ISG) transcription induced by phosphorylated STAT1 enhances immune response and inhibits tumor proliferation. Phosphoinositide 3-kinase (PI3K)-AKT pathway promotes activation of STAT1. Constant exposure to IFN-γ by anti-PD-1/PD-L1 results in survival selective pressure. Accumulated IFN-γ signaling pathway mutation or epigenetic alteration abrogates CD8⁺ T cell mediated tumor cytotoxicity

Fig. 3

Mechanisms of main biomarkers predicting efficacy of PD-1/PD-L1 inhibitors. Firstly, PD-L1 status reflects adaptive immune resistance which is therapeutic target of PD-1/PD-L1 inhibitors. Mismatch repair deficiency (dMMR) and high microsatellite instability (MSI-H) correlates strongly with high tumor mutational burden (TMB). In the meanwhile, TMB enhances the immunogenicity. Thirdly, tumor infiltrating lymphocyte (TIL) represents potential immune surveillance which could be reactivated by agents. Specific gut microbiota promotes differentiation of T cell, as well as lymphocyte homing and recirculation. Besides, peripheral CD14⁺CD16⁻HLA-DR^hi monocyte promotes migration of T cell to tumor bed. Lastly, variation of circulating tumor DNA (ctDNA) and PD-L1⁺ circulating tumor cell presents effect of agent in early stage