Table 1.
Predictive biomarkers for resistance to immune checkpoint inhibitors in NSCLC
| BioMarker | Treatment | Population | Methods | Findings associated with resistance | Ref. |
|---|---|---|---|---|---|
| TMB | Anti-PD-/PD-L1; Anti-PD-1/PD-L1 + anti-CTLA-4 | Advanced NSCLC | WES; NGS gene panels; Tissue and blood samples | Low mutational burden correlates with poor response, reduced OS and PFS | [18,20,22,27] |
| Tumor neoantigen burden | Pembro | LUAD | WES, tissue samples | Low neo-antigen burden correlates with poor OS | [30] |
| Intra-tumor neoantigen heterogeneity | Pembro | Early stage NSCLC | WES; resected NSCLC | High intra-tumor neo-antigen heterogeneity correlates with poor OS | [30] |
| TILs | Pembro; Nivo | Advanced NSCLC | Anti-CD4; anti-CD8 IHC staining; tissue samples | Low CD8+ T-cells density and CD8+/CD4+ ratio correlate with poor response | [44] |
| PDL-1 | Anti-PD-1/PD-L1 | NSCLC | Anti-PD-L1 IHC staining of tumor cells, immune cells; PDL1 mRNA; tissue samples | Low PD-L1 density expression predicts poor response, PFS and OS | [2,8,43] |
| Alternative IC | Anti-PD-1/PD-L1 | NSCLC | Multiparametric FACS detecting alternative IC on CD8+ TILs at baseline/after ICI | Co-expression of alternative IC is associated with primary and secondary resistance | [61,62] |
| IFN-ɣ | Pembro; Nivo; Durva | Advanced NCLC | Gene panels transcription; tumor sample | Decreased IFN-γ expression correlates with poor response and OS | [41,42] |
| IDO | Nivo | Advanced NCLC | Liquid chromatography and mass spectrometry; plasma samples at baseline | High kynurenine/tryptophan ratio and quinolinic acid level associated with poor response | [50] |
| Microbiota | Nivo | Advanced NCLC | Shotgun metagenomic analysis of feces at baseline | Low metagenomic species richness and distinct profiles correlate with poor response | [74] |
| Circulating tumor-reactive CD8+ clones | Pembro; Nivo | Metastatic NSCLC | FACS on blood samples; TCR sequencing | Decreased number of circulating clones correlates with secondary resistance | [32] |
| Alternative immune checkpoints | Pembro; Nivo | Advanced NSCLC | CTLA-4, GITR, and OX40 fluorescence on CD4+ and NK cells; blood samples | Stability of CTLA-4, GITR, and OX40 fluorescence after 1st cycle correlates with primary resistance | [66] |
IC: immune checkpoints; NSCLC: non-small cell lung cancer; NK: natural killers; GITR: glucocorticoid-induced tumor necrosis factor receptor; TCR: T-cell receptor; IDO: indole 2,3-dioxygenase; OS: overall survival; ICI: immune checkpoint inhibitors; IFN-γ: interferon-gamma; PD-L1: programmed death ligand-1; TILs: tumor-infiltrating lymphocytes; PFS: progression-free survival; IHC: immunohistochemistry; WES: whole exome sequencing; NGS: next generation sequencing; TMB: tumor mutational burden; FACS: fluorescence-activated cell sorting; LUAD: lung adenocarcinoma