Table 3.
Senescence-induced therapies and immunotherapy response in cancer
| Senescence-inducing therapy type | Therapy | Cancer and model | Senescence biomarkers | Potential immune response | Potential tumor response | Reference |
|---|---|---|---|---|---|---|
| Radiotherapy | radiotherapy | osteosarcoma mouse model | SA-β-gal, p16, p21, SASP (IL-6, CCL2/3/4/5) | increase NKT activation ↑ | ↓ | [111] |
| radiotherapy | NSCLC human cell line xenografts | SA-β-gal, STING, NF-κB, L1, p21, SASP (IFN-β, IL-1α, IL-6) | increase macrophage activation ↑ | ↓ | [112] | |
| radiotherapy + PARPi (ex vivo in tumor cells) | (1) melanoma; (2) PDAC syngeneic transplant mouse models | SA-β-gal, p16, p21, SASP (CCL5, IFN-β, CXCL9/10/11) | increase DC, CD8+ T, NK activation ↑ | ↓ | [113] | |
| Chemotherapy | cyclophosphamide | B-cell lymphoma syngeneic transplant mouse model | SA-β-gal, NF-κB, p15, SASP (IL-6, IL-8, ICAM-1, CXCL1) | increase NK activation ↑ | ↓ | [114] |
| doxorubicin or melphalan | MM syngeneic transplant mouse model | SA-β-gal, p16, p53, NK ligands (RAE-1, MICA, MULT-1, PVR) | increase NK activation ↑ | ↓ | [115] | |
| cisplatin + irinotecan (ex vivo in tumor cells) | ovarian cancer syngeneic transplant mouse models | SA-β-gal, STING, p16, yH2AX, SASP (IL-6, VEGFA, GM-CSF) | increase DC, CD8+ T activation ↑ | ↓ | [116] | |
| docetaxel | PCa GEMM | SA-β-gal, p16, p21, SASP (GM-CSF, CSF-1, IL-10, CCL2, CXCL1/2) | (1) increase MDSC activation ↑; (2) decrease NK, CD8+ T activation ↓ | ↑ | [117] | |
| mitoxantrone, other agents | (1) PCa human xenografts; (2) PCa clinical samples | SA-β-gal, p16, SASP (IL-6, IL-8, MMPs, AREG), PD-L1 | decrease CD8+ T activation ↓ | ↑ | [118] | |
| Aurora kinase inhibitors | MLN8054/MLN8237 (AURKAi) | (1) melanoma human xenografts; (2) PDXs; (3) syngeneic | SA-β-gal, NF-κB, SASP (IL-6, IL-8, CCL5, CXCL1/2) | increase macrophage, CD8+ T activation ↑ | ↓ | [119] |
| MLN8237 (AURKAi) | melanoma patient samples | SASP (CCL5) | increase CD8+ T activation ↑ | unclear | [119] | |
| AZD1152 (AURKBi) | (1) melanoma; (2) CRC syngeneic transplant mouse models | SA-β-gal, p21 | increase CD8+ T activation ↑ | no significant change | [120] | |
| Cell Cycle inhibitors | abemaciclib (CDK4/6i) | (1) ER + breast cancer GEMM; (2) PDXs | SA-β-gal, MHC-I | (1) increase CD8+ T activation ↑; (2) decrease Treg response ↓ | ↓ | [121] |
| abemaciclib (CDK4/6i) | melanoma syngeneic transplant mouse models | SA-β-gal, SASP (CCL20, CX3CL1) | release T-cell suppression ↓ | no significant change | [122] | |
| palbociclib (CDK4/6i) + trametinib (MEKi) | LUAD GEMM | SA-β-gal, NF-κB, p15, SASP (TNF-α, ICAM-1, IL-15, NKG2D ligands) | increase NK activation ↑ | ↓ | [36] | |
| palbociclib (CDK4/6i) + trametinib (MEKi) | PDAC GEMM | SA-β-gal, SASP (VEGFs, PDGFs, MMPs, IL-6, CXCL1, CCL5), MHC-I, PD-L1 | increase CD8+ T activation ↑ | no significant change | [37] | |
| palbociclib (CDK4/6i) (ex vivo in fibroblasts) | melanoma syngeneic transplant mouse models | SA-β-gal, NF-κB, p16, SASP (IL-6, MMP3, CCL6, CCL8, CCL11) | increase MDSCs activation ↑ | ↑ | [123] | |
| XL413 (CDC7i) | (1) HCC GEMM; (2) human xenografts | SA-β-gal, p16 | increase Mac, CD8+ T, CD4+ T activation ↑ | ↓ | [124] | |
| Pro-senescence + Immunotherapy | cisplatin + irinotecan (chemotherapy) + a-PD-1 ICI | ovarian cancer syngeneic transplant mouse models | SA-β-gal, STING, p16, yH2AX, SASP (IL-6, VEGFA, GM-CSF) | increase CD8+ T, DC infiltration ↑ | ↓↓ | [116] |
| Mitoxantrone (chemotherapy) + a-PD-1 ICI | PCa human xenografts | SA-β-gal, p16, SASP (IL-6, IL-8, MMPS, AREG), PD-L1 | increase CD8+ T infiltration ↑ | ↓ | [118] | |
| MLN8237 (AURKAi) + a-CD137 (T cell agonist) | melanoma syngeneic transplant mouse models | SA-β-gal, NF-κB, SASP (IL-6, IL-8, CCL5, CXCL1/2) | increase CD8+ T infiltration ↑ | ↓↓ | [119] | |
| AZD1152 (AURKBi) + a-CTLA-4 ICI | (1) melanoma; (2) CRC syngeneic transplant models | SA-β-gal, p21 | increase CD8+ T infiltration ↑ | ↓ | [120] | |
| abemaciclib (CDK4/6i) + a-PD-1 ICI | ER + breast cancer GEMM | SA-β-gal, MHC-I | increase CD8+ T infiltration ↑; decrease Treg activation ↓ | ↓↓ | [121] | |
| abemaciclib (CDK4/6i) + a-PD-1/CTLA-4 ICI | melanoma syngeneic transplant mouse models | SA-β-gal, SASP (CCL20, CX3CL1) | release T-cell suppression ↓ | ↓ | [122] | |
| palbociclib (CDK4/6i) + trametinib (MEKi) + a-PD-1 ICI | PDAC GEMM | SA-β-gal, NF-κB, SASP (VEGFs, MMPs, PDGFs, IL-6, CXCL1, CCL5), MHC-I, PD-L1 | increase CD8+ T activation ↑ | ↓ | [123] |
SA-β-gal senescence-associated beta-galactosidase, SASP senescence-associated secretory phenotype, NSCLC non-small cell lung cancer, PDAC pancreatic ductal adenocarcinoma, NKT Natural Killer T cell, DC dendritic cell, NK Natural Killer cell, PCa prostate cancer, GEMM genetically engineered mouse model, MDSC myeloid-derived suppressor cell, AURKA Aurora Kinase A, AURKB Aurora Kinase B, PDX patient-derived xenograft, CRC colorectal cancer, ER estrogen receptor, HCC hepatocellular carcinoma, ICI immune checkpoint inhibitor, LUAD lung adenocarcinoma, MM multiple myeloma, i inhibitor (Mainly from 10.1016/j.semcancer.2022.02.005)