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Immune checkpoint blockade (ICB) has become a major treatment for lung cancer. Better understanding of the tumor immune micro-environment (TIME) in non-small cell lung cancer (NSCLC) is urgently needed to better treat it with this type of therapy. In this review, we describe and explore how NSCLC’s TIME relates to response to ICB, as well as how to treat those with unresponsive types of TIME, which will significantly impact future research in lung cancer immunotherapy.
References | Method | Criteria | TIME Classification | Major Features | Additional Features |
---|---|---|---|---|---|
Herbst et al. [19] | IHC | PD-L1 expression | Responsive | Before Rx | Before Rx |
(TC and IC) | Increased PD-L1 expression | Increased expression of another checkpoint (NSCLC): | |||
CD8+ T cell infiltration | (TC, IC) | B7-H3, CTLA-4, TIM3, LAG3, IDO1, PD-L2 | |||
Decreased CX3CL1; increased CTLA-4 | |||||
Increased IFN-γ and IFN-γ-inducible genes (e.g., IDO1 and CXCL9) | |||||
After Rx | After Rx | ||||
Increased PD-L1 expression | Increased tumor IFN-γ expression | ||||
(TC, IC) | Gene expression pattern of immune activation: | ||||
CD8 and Th1 T cell activation | granzyme-A, B; Perforin, EOMES, IFN-γ, TNF | ||||
CXCL10, CD8A, CTLA 4 | |||||
Non-Responsive | Pre-Rx and After Rx | After Rx | |||
Immunological ignorance | Little or no TILs | No overexpression of genes associated with immune activation | |||
Non-functional immune response | TIL without PD-L1 expression | No overexpression of genes associated with immune activation | |||
(with pre-treatment CD 8 T cell infiltrate) | |||||
Excluded infiltrate | Immune infiltrate at tumor margin | Same as the two types above, except with increased CTLA-4 expression | |||
Proliferation and PD-L1 expression in immune cells at tumor margin | |||||
Teng et al. [24] | IHC | PD-L1 expression (TC) | Type I (adaptive immune resistance) | PD-L1 (+), TIL (+) | Immunogenic mutations associated with |
TILs | increased TILs of higher PD-1, CTLA-4 expression | ||||
Type II (immune ignorance) | PD-L1 (-), TIL (-) | No pre-existing T cell infiltration | |||
Type III (intrinsic induction) | PD-L1 (+), TIL (-) | More common in oncogenic mutation-driven NSCLC | |||
LUAD: PD-L1 expression-associated EGFR mutations | |||||
Type IV (tolerance) | PD-L1 (-), TIL (+) | Increased myeloid cells | |||
Activation of other immune checkpoints and suppressive pathways |
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 |
TIME Subtype | Neoantigen-Related Driver Mutations | Enrichment |
---|---|---|
Wound healing | KRAS, KRAS G12, PIKC3A, TP53 | APC (OM), JAK1 (OM), TP53 *, FAT1, PPP2R1A, BRCA1, RB1, PIK3CA (OM), PTPRD, SPTA1, CTNNB1 *, FGFR3 * (OM), SMARCA4, KRAS G12, DACH1, PTEN *, SMARCA1, JAK1, KRAS *, MSH3 |
IFN-γ-dominant | PIKC3A, TP53 | CASP8, HLA-A, HLA-B, ZNF750, TP53 *, MLH1, NF1 *, FAT1, PPP2R1A, BRCA1, RB1 *, PIK3CA(OM), PTPRD, SPTA1, DACH1 |
Inflammatory | BRAF | BRAF, CDH1 (OM), PBRM1 * |
Lymphocyte-depleted | IDH1 | EGFR (OM), CTNNB1 * |
Immunologically quiet | TP53, IDH1 | IDH1 R132H, ATRX, CIC *, TP53 * |
TGF-β-dominant | KRAS G12 | KRAS G12 |