Table 2.
Biomarkers of Radiotherapy and Immunotherapy Efficacy in NSCLC.
| Biomarker | Sample origin | Treatment | Results | References | |
|---|---|---|---|---|---|
| ↑PD-L1 | FFPE/surgical specimen | ICIs | ↑ OS, PFS | (65–67) | |
| TILs | ↑CD8+ TIL | FFPE | CCRT | ↑PFS, OS | (68, 69) |
| ↑TIL density≥10% | H&E–stained sections | nivolumab | ↑ survival | (70) | |
| ↑PD-1 +CD8+T cells | fresh tumor specimens | durvalumab | ↑ORR, OS, PFS | (71) | |
| ↓PD-1 +CD8+T cells | FFPE | nivolumab | ↑OS, DFS and response | (72) | |
| ↑CD8×PD-L1 signature | FFPE | durvalumab | ↑response | (73) | |
| ↑PD-L1high Tregs | peripheral blood, FFPE from surgery and biopsy | pembrolizumab/nivolumab | ↑response, PFS | (71) | |
| Immune related gene expression profiling (GEP) | ↑18-gene T cell–inflamed GEP | FFPE | pembrolizumab | ↑response rates, PFS | (74) |
| ↑4-gene IFN γ positive (IFN γ+) signature | FFPE/frozen biopsies | durvalumab | ↑ORR, median PFS and OS | (75) | |
| Profile of 24 chemokines and immunosuppressive molecules | FFPE | pembrolizumab | differentiate responders from non-responders, with predictive correlation up to 85.0% | (76) | |
| ↑antigen processing machinery (APM) score | FFPE | ICIs | ↑DFS, OS | (77) | |
| ↓EMT (more epithelial)/↑ Inflammation signature score | FFPE | ICIs | ↑response, PFS, OS | (78) | |
| Radiosensitivity signature (RSS) | 31 gene-signature ( PD-L1-high-RR group) | NCl-60 | RT | ↓survival (Not validated in NSCLC) | (79–81) |
| RSS+IMS (radiation-sensitive + immune-effective) | fresh frozen tumors | RT | ↑DSS, response (Not validated in NSCLC) | (82) | |
| ↑TMB | FFPE/surgical specimen | ICIs | ↑response | (83–85) | |
| FFPE | RT | ↑durable survival | (86) | ||
| Peripheral blood cell and lymphocyte ratios | ↑ALC | full blood | RT | ↑Abscopal effect | (87) |
| ↑ALC | full blood | Nivolumab | ↑PFS, OS | (88) | |
| ↑PD-1+ CD8+ T cells | full blood | pembrolizumab | ↑RR, PFS, OS | (89) | |
| nivolumab | |||||
| atezolizumab | |||||
| ↑CD56+ NK | full blood | ICIs | ↑response | (90) | |
| ↑pre-NLR> 3.6 | full blood | SBRT | ↑mortality | (91) | |
| ↑post-NLR>6 | full blood | SRS | ↓OS | (92) | |
| Poor LIPI (pre-dNLR >3+LDH >upper limit of normal ) | full blood | Atezolizumab/nivolumab | ↓OS, PFS, DCR | (93–95) | |
| NLR-low/TMB-high | full blood | ↓OS, PFS, response rate | (96) | ||
| ctDNA | ↓ctDNA | full blood | ICIs | ↑PFS, OS | (97, 98) |
| cfDNA >20% at the sixth week | full blood | nivolumab | ↓OS, TTP | (99) | |
| miRNA signature classifier (MSC) | ↑post-NLR>6 | full blood | SRS | ↓OS | (92) |
| Poor LIPI (pre-dNLR >3+LDH >upper limit of normal ) | full blood | Atezolizumab/nivolumab | ↓OS, PFS, DCR | (93–95) | |
| NLR-low/TMB-high | full blood | ↓OS, PFS, response rate | (96) | ||
| PD-L1+immune-related MSC risk level | Plasma and tissue samples | ICIs | identify the subgroup of patients with the worst ORR, PFS, OS | (100) | |
| Imaging Biomarkers | ↑pre-TMTV> 75 cm3+ pre-dNLR > 3 | PET/CT | ICIs | ↓OS, DCB | (101) |
| ↑IMPI=2: post-NLR < 4.9+ post-TLG < 541.5 (at the first restaging during ICI treatment ) | PET/CT | ICIs | ↓OS, PFS | (102) | |
| ↓pre-SUVmax <5, pre-SUVmean<3.5 | PET/CT | SABR | ↑complete response at 6 months | (103) | |
| ↑pre-MTV, pre-TLG | PET/CT | high-dose RT | ↓OS | (104) | |
| ↓ΔTLG-TN | PET/CT | RT | ↓3 year-LCR, DSS | (105) | |
| ↑pre-textural feature dissimilarity | PET/CT | SBRT | ↑DSS, DFS (cut point: 18 and 18.4 respectively) | (106) | |
| ↑radiomic features (model 1: Information Correlation 2 from PET+ flatness from CT; model 2: Information Correlation 2 and strength from PET) | PET/CT | SBRT | ↓ local control | (107) | |
FFPE, formalin-fixed paraffin-embedded; ICIs, immune checkpoint inhibitors; RT, radiotherapy; CCRT, concurrent chemoradiotherapy; SBRT, stereotactic Body Radiotherapy; SABR, stereotactic ablative radiotherapy; SRS, stereotactic radiosurgery; OS, overall survival; PFS, progression free survival; TTP, time to progression; DFS, disease free survival; DCB, disease clinical benefit; ORR, overall response rates; DSS, disease specific survival; DCR, disease control rate; LCR, local control rate; EMT, epithelial mesenchymal transition; NCl-60, National Cancer Institute panel of 60 cell lines; SF2, survival fraction at 2 Gy; IMPI, immune-metabolic-prognostic index, ↑ increased; ↓ decreased.