TABLE 2.
Potential mechanisms affecting the efficacy of ICIs on EGFR‐mutant tumors
| EGFR/EGFR‐TKIs | Key indicators | Methods | Main mechanism and result | Reference |
|---|---|---|---|---|
| EGFR | PD‐L1 expression ↓ | Experimental data | EGFR signaling inhibits PD‐L1 expression regulated by IFN‐γ via IRF1 in vitro experiments using human cell lines | [41] |
| Clinical studies | Via the analyses of TCGA and GCLI and IHC | [43, 44, 45] | ||
| PD‐L1+/TIL+ ↓ | Clinical studies | NA | [45] | |
| PD‐L1+ T cells in the blood ↓ | Clinical studies | NA | [50] | |
| PD‐L1 expression ↑ | Experimental data | Via the downstream signaling pathway of EGFR, such as MAPK/ERK/c‐Jun, Hippo/YAP, or JAK/STAT3 | [37, 38, 39] | |
| TMB ↓ | Clinical studies | NA | [55, 105, 106] | |
| CD8+ T cells ↓ | Experimental data | Downregulation of CXCL10 inhibits effector CD8+ T cell recruitment mediated by the PI3K‐AKT pathway | [45, 61] | |
| Tregs ↑ | Experimental data | EGFR signaling upregulates Treg‐associated genes | [65] | |
| Experimental data | Upregulate CCL22 via the JNK‐c‐Jun pathway | [41] | ||
| Experimental data | Mediate the function of Treg through amphiregulin | [66, 67] | ||
| Experimental data | Facilitate the conversion of CD3+CD4+CD25− T cells to Tregs via IDO | [68] | ||
| MHC class I | Experimental data | MHC class I ↓; via IFN‐γ signaling pathways and MEK/ERK signaling pathways | [69, 70, 71] | |
| TAMs | Experimental data | Activate the EGFR signaling via EGF; Recruiting more Treg cells by producing chemokines | [72] | |
| CD73 | Experimental data | Upregulate CD73 expression via the Ras‐RAF‐ERK pathway | [35, 78, 79] | |
| Clinical studies | Tregs ↑, CD4+ TIL ↓, CD8+ TIL ↓ | [78] | ||
| Experimental data | CD73 blockade significantly inhibited tumor progression in the immune‐competent mouse model | [35] | ||
| EGFR‐TKIs | PD‐L1 expression | Experimental data | PD‐L1 expression↓ | [46] |
| Clinical studies | PD‐L1 expression↓ | [47, 48, 49] | ||
| Immunological enhancement (early stage) | Experimental data | CD8+ TIL ↑, DCs ↑, M1‐like TAMs ↑, Treg ↓ | [46] | |
| Immunosuppressive (later stage) | Experimental data | IL‐10 ↑, CCL2 ↑, MDSCs ↑ | [46] |
Abbreviations: ICI, immune checkpoint inhibitor; EGFR, epidermal growth factor receptor; TIL, tumor‐infiltrating lymphocyte; PD‐L1, programmed death‐ligand 1; TIL, tumor‐infiltrating lymphocyte; TMB, tumor mutational burden; Treg, regulatory T cell; MHC, major histocompatibility complex; TAM, tumor‐associated macrophage; IFN‐γ, interferon‐gamma; IRF1, interferon regulatory factor 1; TCGA, The Cancer Genome Atlas; IHC, immunohistochemistry; NA, not applicable; CXCL10, CXC‐chemokine ligand 10; CCL2, C‐C chemokine ligand 2; MDSC, myeloid‐derived suppressor cell; IL‐10, interleukin‐10; IDO, indoleamine 2, 3‐ dioxygenase.