Table 1.
A characteristic comparison of lung adenocarcinomas with different patterns of KRAS mutation.
| Groups | ‘KRAS-only’ | KRAS/LKB1 co-mutation | KRAS/TP53 co-mutation | KRAS/LKB1/TP53 tri-mutation |
|---|---|---|---|---|
| Characteristics | ||||
| Mutation frequency in KRAS groupRef. | 37–50%14,16,17 | 8–31%14,16,17 | 31–46%14,16,17 | 11–19%18,19 |
| Sensitivity to glucose restriction (versus wild-type KRAS)Ref. | ↑20,21 | ↑↑21 | ↑↑20 | NR |
| Aggression of cancer cell (versus wild-type KRAS)22 | ↑ | ↑↑↑ | ↑↑ | NR |
| Percent of tumour positive for PD-L1 expression23 | 37.5% | 10% | 68.8% | 25% |
| Median TMB value16 | 8.1–11.7 mutations/Megabase in these three groups | NR | ||
| Tumour immune milieuRef. | 1. Certain numbers of CD4+ T,24 CD8+ T,25,26 Treg,16,26 γδT,26 and myeloid cells (including neutrophils and macrophages)26
2. CXCL-9 and CXCL-10 upregulation26 3. CXCL-2, IL-6 and TGF-β downregulation26 |
1. Massive neutrophils with immune-suppressive function24,27
2. Few CD3+ T,14,16,24,27 CD4+ T,24 CD8+ T,14,16,24,27 CD45RO+ T,14,16 CD68+ macrophages24,27 and matured DC;27 3. Low proliferation activity of CD4+ T and CD8+ T24 4. Low potency of immune surveillance28 5. Low production of IFN-γ by CD4+ T, or by CD8+ T24 6. G-CSF, IL-1α, IL-6 and CXCL-724 7. STING inactivation29 8. HLA-DR, CD28, ICOS, CD80 and CD86 downregulation14 9. PD-1, CTLA-4, TIM-3 and LAG-3 downregulation in tumors14,18 10. CD4+ or CD8+ T-cell exhaustion24 |
1. Certain numbers of NK,26 B cell,26 matured DC,27 Treg16,26 and macrophages27
2. Massive CD3+ T, CD8+ T, and CD45RO+ T13,14,16,27 3. CCL-5, CXCL-9, CXCL-10, CXCL-11 and CXCL-13 upregulation in tumours27 4. HLA-DR, CD28, ICOS, CD80 and CD86 upregulation in tumours14,18 5. PD-1, CTLA-4, TIM-3 and LAG-3 upregulation in tumours14,18 6. Antigen presentation↑16,18 7. Antigen recognition↑14 8. T-cell-driven cytotoxicity↑14,27 |
1. CXCL-7, G-CSF and IL-6 upregulation24- Increased amounts of neutrophils with immune-suppressive function 2. CD28, CD86, CTLA-4, TIM-3 and HLA-DR downregulation in tumours18- Reduced amounts of T cells in tumours 3. PD-L1 upregulation18,23- T-cell exhaustion |
| Prognosis after first-line therapy Single-centre data18,19 |
• Upenn data*
Median PFS: NM Median OS: NM • CSU data& Median PFS: 22.29 weeks Median OS: 28.57 weeks |
• Upenn data*
Median PFS: 2.4 months Median OS: 7.1 months • CSU data& Median PFS: 12.43 weeks Median OS: 19.36 weeks |
• Upenn data*
Median PFS: NM Median OS: NM • CSU data& Median PFS: 12.86 weeks Median OS: 16.29 weeks |
Upenn data*
Median PFS: 13 months Median OS: 22 months • CSU data& Median PFS: 12.29 weeks Median OS: 20.22 weeks |
| ORR to immune checkpoint blockade therapy • SU2C cohort16 (MSKCC+MDACC+MGH) |
28.6% | 7.4% | 35.7% | NR |
| CheckMate-057 cohort16 | 18.2% | 0% | 57.1% | NR |
| • KEYNOTE-04230
(PD-L1 ⩾ 1%) |
31% (LKB1 mutation: n = 16 patients) versus 29% (LKB1 wide-type: n = 214 patients) | |||
| Prognosis after immune checkpoint blockade therapy • SU2C cohort16 (MSKCC+MDACC+MGH) • CheckMate-057 cohort16 |
Median PFS: 2.7 months Median OS: 16.1 months Median PFS: 2.1 months Median OS: ~7 months |
Median PFS: 1.8 months Median OS: 6.4 months Median PFS: 2.0 months Median OS: ~27 months |
Median PFS: 3.0 months Median OS: 16.0 months Median PFS: 5.1 months Median OS: ~15 months |
Median PFS: NR
Median OS: NR Median PFS: NR Median OS: NR |
| • KEYNOTE-04230
(PD-L1 ⩾ 1%) |
LKB1 mutation Median PFS: 5 months Median OS: 18 months |
LKB1 wide-type Median PFS: 6 months Median OS: 17 months |
||
| PD-L1/TIL paradigm31 | Positive/Positive | Negative/Negative | Positive/Positive | Positive/Negative |
| Precision of mutational pattern in predicting ICI response as tumoral PD-L1 expression increasing Ref. | Increase16,32,33 | Increase30 | Increase16,32 | NR |
Over 80% of enrolled patients receiving chemotherapy during first-line management.
Chemotherapy by using pemetrexed plus platinum regimen.
CCL-5, chemokine C-C motif ligand-5; CSU, XiangYa School of Medicine; CTLA-4, cytotoxic T-lymphocyte associated protein-4; CXCL, chemokine C-X-C motif ligand; G-CSF, granulocyte-colony stimulating factor; HLA-DR, human leukocyte antigen (locus) DR; ICI, immune checkpoint inhibition; ICOS, inducible T-cell co-stimulator; IFN-γ, interferon-gamma; KRAS, Kirsten rats sarcoma viral oncogene homolog; LAG-3, lymphocyte-activation gene-3; LKB1, liver kinase B1 gene; MDACC, MD Anderson Cancer Centre; MGH, Massachusetts General Hospital; MSKCC, Memorial Sloan-Kettering Cancer Centre; NR, not reported; OS, overall survival; PD-1, programmed death-1; PD-L1, programmed death-ligand 1; PFS, progression-free survival; STING, stimulator of interferon genes; TGF-β, transforming growth factor-beta; TIL, tumour-infiltrating lymphocyte; TIM-3, T-cell immunoglobulin and mucin domain-containing molecule-3; TMB, tumour mutation burden; TP53, tumour protein-53 gene; UPenn, University of Pennsylvania.