Table 2.
The major hallmarks and mechanisms of Tumor Immune Escape in the TME of EGFR-mutated non-small cell lung cancer.
| Mechanism of action | Population(s)/pathway(s) | Effect(s) on TME |
|---|---|---|
| Tumor-infiltrating lymphocytes (TIL)s | CD3+ lymphocytes CD8+ T-cells CD4+ T-cells | Inefficacy tumor-cytotoxicity of T-cells |
| Over-expression of inhibitory immune checkpoints | ↑ CTLA-4, PD-1, LAG3, TIM3, VISTA, TIGIT | Inhibition of T-cell function/T-cell anergy |
| Over-expression of immune checkpoint ligands | PD-L1 PD-L2 | Activation of inhibitory immune checkpoints |
| Defective recognition of lung cancer cells | Downregulation, mutation or loss of MHC class I Lung cancer antigens Defective antigen presentation | ↓ Initiation of the antigen-specific immune response, antigen processing and presentation, and the cross-priming processesInefficacy activation of lung cancer infiltrating T-cells |
| Up-regulation of immune suppressive cells | MDSCs CD4+CD25+FoxP3+ Tregs Macrophage infiltration (M2-TAM) | Inhibition of T-cell function Direct pro-tumorigenic effect (VEGF, TGF-β) |
| Release of pro-tumorigenic and pro-angiogenic factors by TME | TGF-β VEGF, IL-10, IL-6, MMP CCL-2 iNOS | Induction of both recruitment and accumulation of immunosuppressive cells Tumor angiogenesis and stroma remodeling Migration of MDSCs in the TME through STAT3 activation Inhibition of T-cell function |
| Intracellular activation of EGFR signaling | ↑ JAK/STAT3 ↑ PI3K/AKT/mTOR ↑ Ras/RAF/MEK/ERK ↑ NF-kB | ↓ Down-regulation of MHC I/II class - ↓ Inhibition of STAT1 activity↑ MDSCs - ↓ DCs and APCs - ↑ TAM-M2 polarization↑/↓ PD-L1; ↓ IFNγ signature↑ Production and release of negative modulators (TGF-β, IDO, CCL-2) |
| Tumor mutational load and Neoantigens | ↓ TMB | Low TMB may negatively influence the immune-mediated anti-tumor response |
| Dysregulation of the immunometabolism | ↑ CD39/CD73 – adenosine signaling ↑ IDO ↑ ARG-1 | ↑ Immunosuppressive TME restraining anti-tumor immunity through A2AR↑ Degradation of tryptophan into immunosuppressive kynurenines↑ TAM-M2 polarization |
TME, tumor microenvironment; mAb, monoclonal antibody; EGFR, epidermal growth factor receptor; NSCLC, Non-Small-Cell Lung Cancer; MHC, major histocompatibility complex; CTLA4, cytotoxic T-lymphocyte antigen 4; PD-1, programmed death 1; LAG3, lymphocyte activation gene-3; TIM3, T cell immunoglobulin and mucin domain 3; VISTA, V-domain immunoglobulin suppressor of T-cell activation; PDL1, programmed death ligand 1; PDL2, programmed death ligand 2; IFN, interferon; MDSCs, myeloid-derived suppressor cells; Tregs, regulatory T cells; TAM, tumor-associated macrophages; MMP, matrix metalloproteinase; CCL-2, CC chemokine ligand-2; TGF, tumor necrosis factor; VEGF, vascular endothelial growth factor; iNOS, inducible nitric oxide synthase; IDO, indoleamine 2,3 dioxygenase; IL, interleukin; TMB, tumor mutation burden; A2AR, adenosine 2A receptor; ARG, arginase.