Table 1.
Immune escape and immunosuppressive mechanisms in pre-invasive lesions, in invasive LUAD and LUSC, and in immunotherapy resistance.
| Mechanism | LUAD or Pre-Invasive Lesions | LUSC or Pre-Invasive Lesions | Refs. |
|---|---|---|---|
| 1. Impaired Antigen Presentation | |||
| -HLA-LOH. | -Progressive increase from AIS/MIA to LUAD. |
-Detected in 34% of CIS and 28% of LUSC. | [12,21] |
| -HLA-LOH. | -Detected in 29% of LUAD, frequently subclonal HLA LOH. |
-Detected in 61% of LUSC, frequently subclonal HLA LOH. | [2] |
| -HLA-LOH. | -Detected in 56% of LUAD. | -Detected in 78% of LUSC. | [22] |
| -Expression of MHC I/II, B2M, and antigen processing machinery. -NK cell activation and type I IFN production. |
-Reduced/defective in subgroup 1 of three early LUAD subsets. |
[23] | |
| -Expression of peptide-trimming machinery genes and MHC class II. | -Reduced in subgroup 2 of three early LUAD subsets. |
[23] | |
| -Hypermethylation at chromosome 6 HLA region. | -Detected in progressive CIS lesions. | [21] | |
| -Mutations and copy number changes of genes involved in antigen presentation. |
-More frequent in progressive CIS lesions. | [21] | |
| 2. Neoantigen Loss/Silencing and Neoantigen Subclonal Structure | |||
| -Neoantigen promoter hypermethylation. | -Increased in later stage pre-invasive lesions. -Detected in invasive stage. |
-Detected in invasive stage. | [11,22] |
| -High neoantigen subclonal fraction. | -Associated with ICB resistance. | [24] | |
| -Neoantigen loss by immunoediting or through deletion of chromosomal regions and LOH. |
-Associated with acquired ICB resistance. | -Associated with acquired ICB resistance. | [25] |
| 3. Function of Immune-related Genes and Pathways | |||
| -Genes belonging to the IFN γ and TGF-γ signaling pathways. |
-Downregulated in subgroup 2 of three early LUAD subsets. |
[23] | |
| -CD47, B7-H3, CTLA-4 genes. | -Increased expression from AAH to LUAD. | [14] | |
| -Genes involved in negative regulation of immunity. | -Upregulated in high-grade pre-invasive lesions. | [20] | |
| -Downregulation of CD137L. | -Detected in progressive CIS lesions. | [21] | |
| -Expression of genes involved in inflammation, lymphocyte regulation, antigen processing/presentation. |
-Decreased in “normal-like” precursor lesions. | [26] | |
| -Genes involved in interferon signaling and antigen presentation. | -Downregulated in the “proliferative” pre-invasive lesions that progress to LUSC. | [26] | |
| 4. Immune Structure of the Tumor Microenvironment | |||
| -Immune infiltration. | -Lowest in subgroup 1 of three early LUAD subsets. |
[23] | |
| -Tregs and immunosuppressive cytokines. | -Higher levels in subset of cold tumors. | [27] | |
| -Tregs, tumor-associated neutrophils. | -Present at higher frequency in LUSC compared to LUAD. | [28] | |
| -TH1 and TH17 and macrophages. | -Present at higher frequency in LUAD compared to LUSC. |
[28] | |
| -CD4/CD8 ratio. | -Progressive increase from NL to LUAD. | [12] | |
| -TH1 cytokines. | -Reduced in AIS and MIA vs. AAH. | [12] | |
| -TH2 cytokines. | -Higher in AIS and MIA. | [12] | |
| -CD16+ NK cells, CD8+ CTLs, CD141+ DCs, CD16+ monocytes. |
-Reduced in LUAD compared to NL. | [3] | |
| -Tregs, CTLs, PD-1+ CTLs. PPARγhiCD64hiCD14hiIL-6hi macrophages. |
-Increased in LUAD compared to NL. | [3,27] | |
| -Myeloid cells, neutrophils, macrophages. | -Increase in high-grade dysplasia. | [20] | |
| -Spatial segregation of CD3+ cells and epithelial cells. | -Detected in high-grade lesions. | [20] | |
| -Lymphocytes, CD8+ cells, and IL2, TNF, IL12A, IL23A genes. | -Lower levels in progressive CIS compared to regressive CIS. | [21] | |
| -Immune-cold microenvironment. | -Almost all pre-invasive lesions progress to cancer. | [21] | |
| 5. Genetic Changes Impacting on Immune Escape/Immune Suppression | |||
| -Chromosome-level and arm-level aneuploidy associated with immunosuppressive microenvironment. |
-Associated with ICB resistance. | -Associated with ICB resistance. | [29,30] |
| -KRASmut/LKB1mut LUAD subset. | -Reduced T cell infiltration and PD-L1 expression. -Defective STING expression and impaired type I IFN pathway. -Downregulation of DC, NK, and macrophage signatures. -Associated with ICB resistance. |
[5,31,32] | |
| -EGFR mutations and EML4-ALK fusion LUAD subsets. | -Immune-cold microenvironment. -Lack of T cell infiltration, constitutive PD-L1 expression. -Associated with ICB resistance. |
[4,33,34] | |
AAH: atypical adenomatous hyperplasia; AIS: adenocarcinoma in situ; MIA: minimally invasive adenocarcinoma; LUAD: lung adenocarcinoma; LUSC: lung squamous cell carcinoma; CIS: carcinoma in situ; HLA LOH: HLA loss of heterozygosity; ICB: immune checkpoint blockade.