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Table 3 Senescence-induced therapies and immunotherapy response in cancer

From: Aging microenvironment and antitumor immunity for geriatric oncology: the landscape and future implications

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]

  1. 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 https://doi.org/10.1016/j.semcancer.2022.02.005)