Classification of Non-Small Cell Lung Cancer’s Tumor Immune Micro-Environment and Strategies to Augment Its Response to Immune Checkpoint Blockade
Abstract
:Simple Summary
Abstract
1. Introduction
2. TIME Classification Applicable to NSCLC and Its Correlation with Response to ICB
3. TIME Subtype Classification Based on Analysis of Immunogenomic Data from the Cancer Genome Atlas (TCGA)
4. Potential Biomarkers and Therapeutic Targets in ICI Responsive vs. Nonresponsive TIME with a Focus on NSCLC
5. Therapeutic Strategies to Augment Response to ICI in NSCLC with “Unresponsive” Types of TIMEs
6. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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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 |
TIME Classification | Characteristics/Alterations | Proposed Treatment |
---|---|---|
Tolerance | JAK mutations | ICI + RT, chemotherapy, STING agonists, dsDNA sensing nano-therapy, and/or adoptive T cell transfer |
↑Tregs | ICI + Treg suppressors (e.g., anti-CD25, anti-ST2) ± RT | |
↑MDSCs | ICI + MDSC suppressors (targeted therapies, HDAC inhibitors, CXCR1/2 inhibitors, etc.) | |
↑FasL (MDSC) | ICI + adoptive T cell therapy or antibodies to FasL | |
↑VEGF | ICI + VEGF inhibitors | |
↑TGF-β | ICI + TGF-β inhibitors, fused anti-PD-L1/TGF-β trap | |
↑IDO1 | ICI + IDO1 inhibitors | |
Terminal T cell exhaustion through other immune checkpoints | ICI of multiple/or alternative immune checkpoints, such as LAG-3, TIM-3, TIGIT, and BTLA ± RT ± chemotherapy | |
Immunological Ignorance/Exclusion | ||
Lack of TAAs/immuno-editing | ICI + RT and/or chemotherapy | |
STK11/LKB1, KEAP1 mutations | ICI + glutaminase inhibitors and/or NRF2 inhibitors ± RT, chemotherapy, or other STING activators | |
Wnt/β-catenin mutations | Wnt/β-catenin inhibitors | |
PTEN loss/PIK3CA mutations | PIK3CA inhibitors | |
EGFR mutation (exon 21) | EGFR TKI with ICI at progression; ICI/chemo/inhibitors of other targets/RT combinations | |
EGFR mutation (other) | ICI/chemo/inhibitors of other targets/RT combinations | |
ALK or RET re-arranged | ICI/chemo/inhibitors of other targets/RT combinations | |
↑Angiogenesis | ICI + VEGF inhibitors, COX-2 inhibitors, or FasL antibodies ± chemotherapy | |
↑TGF-β | As above |
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Chi, A.; He, X.; Hou, L.; Nguyen, N.P.; Zhu, G.; Cameron, R.B.; Lee, J.M. Classification of Non-Small Cell Lung Cancer’s Tumor Immune Micro-Environment and Strategies to Augment Its Response to Immune Checkpoint Blockade. Cancers 2021, 13, 2924. https://doi.org/10.3390/cancers13122924
Chi A, He X, Hou L, Nguyen NP, Zhu G, Cameron RB, Lee JM. Classification of Non-Small Cell Lung Cancer’s Tumor Immune Micro-Environment and Strategies to Augment Its Response to Immune Checkpoint Blockade. Cancers. 2021; 13(12):2924. https://doi.org/10.3390/cancers13122924
Chicago/Turabian StyleChi, Alexander, Xia He, Lin Hou, Nam P. Nguyen, Guangying Zhu, Robert B. Cameron, and Jay M. Lee. 2021. "Classification of Non-Small Cell Lung Cancer’s Tumor Immune Micro-Environment and Strategies to Augment Its Response to Immune Checkpoint Blockade" Cancers 13, no. 12: 2924. https://doi.org/10.3390/cancers13122924