Table 2.
Characteristics the TCGA TIME subtype classification.
| TIME Subtypes | Wound Healing ǂ | IFN-γ Dominant | Inflammatory | Lymphocyte Depleted | Immunologically Quiet | TGF-β Dominant |
|---|---|---|---|---|---|---|
| Leukocyte fraction * | Intermed. | High | Intermed. | Low | Low | Highest |
| Lymphocyte fraction (25–55%) | High | Highest | High | Intermed. low | Lowest | Intermed. |
| TIL (H and E) | High | Highest | Intermed. low | Low | Lowest | Intermed. |
| Immune cell composition | ||||||
| T cells | ||||||
| CD8 T cells (<15%) | Intermed. high | Highest | High | Intermed. low | Lowest | Intermed. |
| CD4 T cells (<35%) | ||||||
| Th1 | Lowest | Elevated | Elevated | Elevated | ||
| Th2 | Highest | Highest | Lowest | Intermed. | Low | Intermed. high |
| Tfh (<10%) | High | Highest | Intermed. | Low | Lowest | Intermed. low |
| Tregs (<5%) | High | Highest | Intermed. high | Low | Lowest | High |
| Macrophages (38–60%) | Elevated | Most elevated | Elevated | |||
| M0 (<15%) | Highest | High | Intermed. low | Intermed. | Lowest | High |
| M1 (<10%) | Intermed. | Highest | Intermed. | Intermed. low | Lowest | Intermed. |
| M2 (>20%) | Intermed. low | Lowest | Intermed. | High | Highest | High |
| Tumor proliferation rate | Highest | Highest | Low | High | Lowest | High |
| Survival | ||||||
| OS | Intermediate | Intermediate | Best | Worst | Worse | Worst |
| PFI | Intermediate | Intermediate | Best | Worst | Worse | Worst |
| NSCLC subtype | Predom. in LUSC; third common in LUAD ** | Second most common in LUAD and LUSC | Predom. In LUAD *** | LUSC ** | ||
| Factors of immunogenecity | ||||||
| DNA damage | ||||||
| Tumor neoantigen load | ||||||
| SNVs | Highest | Second highest | Lowest | |||
| Indels | Highest | Second highest | Lowest | |||
| ITH | Elevated | Elevated | Lowest | |||
| Enriched oncogenic driver mutations | APC, JAK1, PIK3CA, FGFR3 | PIK3CA, FGFR3 | CDH1, PIK3CA, FGFR3 | EGFR | ||
| TCR diversity | Intermediate | Highest | Intermediate | Low | Lowest | Highest |
| Immunomodulators | ||||||
| Expression | ||||||
| CXCL10 | Highest | Lowest | Second Highest | |||
| EDNRB | Low | Lowest | Highest | |||
| BTLA | High | High | ||||
| Networks modulating the immune response | ||||||
| Predominant immune cells | CD8 T cells | CD8 T cells, CD4 T cells | CD4 T cells | CD4 T cells | ||
| Intracellular regulatory networks | ||||||
| TGF-β (somatic mut+) | ↓Leuk Fract. | ↑Leuk Fract. | ↓Leuk Fract. | |||
| ↑r DC, M0, M1, M2, r NK, plasma cells | ↑E, a Mast, M0/2, a DC, r NK, TγΔ | ↑M1, M2, N, CD4, Treg | ↑M0,M1, a DC | ↑M0, Treg, mr CD4 | ↑r DC | |
| ↓a NK, Treg, Tfh, CD8 | ↓CD8, Treg, Tfh, a NK | ↓DC, M0, Tfh, m B cells, plamsa cells | ↓monocytes | ↓n CD4, CD8 | ||
| Extracellular comm. networks | ||||||
| IFN-γ (+) | IFN-γ (+) | |||||
| TGF-β (+) | TGF-β, TGF-βR(+) | TGF-β, TGF-βR(+) | ||||
| T cell and macrophage-related signaling | CD80-CTLA4 | LAG-3, CD27/28 | CD27, PD-1 | TLR4, VEGFB | TLR4 | TLR4 |
| CD70-CD27 | TIGIT, ICOS, CTLA, PD-1 | CCR4, 5; CXCR3 DARC | EDN3-EDNRB, CX3CL1-CX3CR1 | ITGB2 | ||
| IL1A/1B-IL1R2 | CXCR3, CCR1,4,5 | CD276 | ||||
| CXCL9-CXCR3 | BTLA |
ǂ associated with high expression of angiogenic genes; a: activated; r: resting; m: mature; n: naïve; * highest in LUSC and LUAD (median: ≈30%); ** decreased survival; *** increased survival; ↑: increased; ↓: decreased.