Introduction
Intracellular changes in senescent cells
Aging type | Changes in phenotypes | Potential consequences |
---|---|---|
Innate immunity | (1) decrease chemotaxis; (2) decrease phagocytosis of debris; (3) decrease antigen presentation ability | (1) inhibit the activation of tumor-specific CD8 + cytotoxic T cells; (2) decrease the diversity of tumor-specific CD8 + cytotoxic T cells |
Immunosenescence | ||
B cells | (1) increase precursor cells; (2) increase proinflammatory B cells (TNF-α +): (3) inhibit antibody production, diversity and avidity | (1) decrease antibody production and diversity; (2) inhibit response to novel tumor antigens; (3) promote inflammation and autoantibody production; (4) increase the possibility of immune-related AEs |
T cells | (1) increase naive T cells; (2) increase Tregs; (3) decrease T-cell repertoire | (1) decrease recognition and responses to novel tumor antigen; (2) increase antigen recall due to large amount of memory T cells |
Bone marrow | (1) increase myeloid lymphoid progenitors; (2) inhibit B-cell maturation | decrease potential adoptive immune response to novel tumor antigens |
Thymus | (1) increase epithelial cell attrition; (2) reduce IL-7; (3) decrease mature T-cell production | (1) decrease the amount of naive T cells; (2) decrease the possibility to recognize novel tumor antigens |
Cellular senescence | (1) decrease telomere length; (2) inhibit cell proliferation; (3) increase expression of cell cycle inhibitors (p16INK4a and P21CIP/KIP); (4) increase proinflammatory cytokine and matrix remodeling factors | (1) decrease the amount of responding B and T cells; (2) promote cancer metastasis; (3) increase the recruitment of immunosuppressive cells (Tregs, MDSCs) |
Inflammaging | (1) increase chronic inflammation; (2) increase the level of IL-6, IL-8, IL-18, TNF-α, CRP | (1) increase tumor mutagenesis via inflammatory mediators; (2) inhibit cytokine production in response to tumor antigens |
Cancer type | Senescent cell | Senescence inducer | Major roles of SASP | SASP factors | |
---|---|---|---|---|---|
Protumorigenic SASP | hepatocyte | hepatocyte | OIS (N-Ras) | (1) myeloid cell recruitment; (2) MDSC differentiation | CCL2 |
hepatocyte | hepatic stellate cell | HFD | antitumor immunity of CD8+ T cells impairment | PGE2 | |
lymphocyte | lymphocyte | TIS (doxorubicin) | stemness induction | not reported | |
mammary epithelial cell | mammary epithelial cell | TIS (doxorubicin) | mitogenic support | Eotaxin, CXCL5, Rantes | |
mammary epithelial cell | fibroblast | DNA damage (bleomycin) | cancer invasion promotion | MMPs | |
mammary epithelial cell | mammary epithelial cell | OIS (HER2) | cancer metastasis promotion | not reported | |
melanocyte | fibroblast | TIS (CDK4/6 inhibitor) | myeloid cell recruitment | not reported | |
mesothelial cell | mesothelial cell | TIS (pemetrexed) | (1) EMT induction; (2) chemoresistance | not reported | |
prostate epithelial cell | prostate epithelial cell | TIS (PTEN loss) | myeloid cell recruitment | CXCL1, CXCL2 | |
prostate epithelial cell | prostate epithelial cell | TIS (PTEN loss) | MDSC recruitment | not reported | |
thyroid follicular cell | thyroid follicular cell | OIS (BRAF) | anoikis resistance | CXCL12 | |
Antitumorigenic SASP | hepatocyte | hepatocyte | OIS (N-Ras) | immune-related senescent cell clearance | IL-1α |
lymphocyte | lymphocyte | TIS (cyclophosphamide) | cellular senescence reinforcement | not reported | |
melanocyte | melanocyte | TIS (AURKA or CDK4/6 inhibitor) | lymphocyte recruitment | CCL5 | |
melanocyte | melanocyte | TIS (Aurora inhibitor) | cellular senescence reinforcement | not reported | |
osteoblast | osteoblast | TIS (radiotherapy) | NKT cell recruitment | IL-6 | |
pancreatic ductal cell | pancreatic ductal cell | TIS (MEK and CDK4/6 inhibitors) | (1) vascularization promotion (2) drug delivery improvement (3) endothelial cell activation (4) CD8+ T-cell accumulation | VEGF, CCL5, CXCL1, IL-6 | |
hepatocyte | hepatocyte | OIS (N-Ras) | (1) myeloid cell recruitment (2) macrophage differentiation | CCL2 |
Changes in cytokines and their receptors
Formation of senescence and SASP
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] |
Changes in association with immune molecules and cells
Changes associated with cell growth
Impact of senescence on the TME
The effects of the ECM
Angiogenesis
Stromal population
Other TME components
Aging and potential response to therapy
Chemotherapy
Targeted therapy
Immunotherapy
Trial name | Year | Intervention and control settings | Participants’ characteristics | Key results and findings |
---|---|---|---|---|
Malignant melanoma | ||||
dacarbazine + ipilimumab versus dacarbazine + placebo (NCT00324155) [338] | 2011 | First line dacarbazine + ipilimumab versus dacarbazine | N = 502; median age = 57 yr; 65 years: 32% | OS ≥ 65 yr, HR: 0.99 (0.56–1.25); OS < 65 yr, HR: 0.67 (0.40–0.87) |
KEYNOTE-006 (NCT01866319) [339] | 2015 | First line or pretreated pembrolizumab versus ipilimumab | N = 834; median age = 62 yr; 65 years: 43% | OS ≥ 65 yr, HR: 0.56 (0.36–0.87); OS < 65 yr, HR: 0.65 (0.44–0.95) |
CheckMate 066 (NCT01721772) [340] | 2014 | First line nivolumab versus dacarbazine | N = 418; median age = 65 yr; 65 years: 52% | OS ≥ 75 yr, HR: 0.25 (0.10–0.61); OS 65–74 yr, HR: 0.44 (0.24–0.81); OS < 65 yr, HR: 0.52 (0.32–0.85) |
CheckMate 067 (NCT01844505) [341] | 2017 | First line nivolumab + ipilimumab versus ipilimumab versus nivolumab | N = 945; median age = 60 yr; 65 years: 40% | OS ≥ 65 yr, HR: 0.69; OS < 65 yr, HR: 0.48 (n + i vs. i); OS ≥ 65 yr, HR: 0.96; OS < 65 yr, HR: 0.78 (n + i vs. n); OS ≥ 65 yr, HR: 0.71; OS < 65 yr, HR: 0.62 (n vs. i) |
CheckMate 238 (NCT02388906) [342] | 2017 | Adjuvant nivolumab versus ipilimumab | N = 906; median age = 55 yr; 65 years: 26% | RFS ≥ 65 yr, HR: 0.66 (0.45–0.97); RFS < 65 yr, HR: 0.65 (0.51–0.84) |
KEYNOTE-054 (NCT02362594) [343] | 2018 | Adjuvant pembrolizumab versus placebo | N = 1019; median age = 54 yr; 65 years: 25% | RFS ≥ 65 yr, HR: 0.55 (0.32–0.93); RFS < 65 yr, HR: 0.57 (0.41–0.80) |
Non-small cell lung cancer | ||||
KEYNOTE-024 (NCT02142738) [344] | 2016 | First line, TPS > 50%, pembrolizumab versus platinum-based chemotherapy | N = 305; median age = 65 yr; 65 years: 54% | OS ≥ 65 yr, HR: 0.64 (0.42–0.98); OS < 65 yr, HR: 0.60 (0.38–0.96) |
KEYNOTE-042 (NCT02220894) [345] | 2019 | First line, TPS > 1%, pembrolizumab versus platinum-based chemotherapy | N = 1274; median age = 63 yr; 65 years: 45% | OS ≥ 65 yr, HR: 0.82 (0.66–1.01); OS < 65 yr, HR: 0.81 (0.67–0.98) |
KEYNOTE-010 (NCT01905657) [346] | 2016 | Pretreated, pembrolizumab versus docetaxel | N = 1034; median age = 63 yr; 65 years: 41% | OS ≥ 65 yr, HR: 0.76 (0.57–1.02); OS < 65 yr, HR: 0.63 (0.50–0.79) |
CheckMate 017 (NCT01642004) [347] | 2015 | Pretreated squamous, nivolumab versus docetaxel | N = 272; median age = 63 yr; 65 years: 44% | OS ≥ 75 yr, HR: 1.85 (0.76–4.51); OS 65–74 yr, HR: 0.56 (0.34–0.91); OS < 65 yr, HR: 0.52 (0.35–0.75) |
CheckMate 057 (NCT01673867) [348] | 2015 | Pretreated non squamous, nivolumab versus docetaxel | N = 582; median age = 62 yr; 65 years: 42% | OS ≥ 75 yr, HR: 0.90 (0.43–0.87); OS 65–74 yr, HR: 0.63 (0.45–0.89); OS < 65 yr, HR: 0.81 (0.62–1.04) |
OAK (NCT02008227) [349] | 2017 | Pretreated, atezolizumab versus docetaxel | N = 850; median age = 64 yr; 65 years: 47% | OS ≥ 65 yr, HR: 0.66 (0.52–0.83); OS < 65 yr, HR: 0.80 (0.64–1.00) |
PACIFIC (NCT02125461) [350] | 2017 | Adjuvant concurrent chemoradiotherapy followed by durvalumab versus placebo | N = 709; median age = 64 yr; 65 years: 45% | OS ≥ 65 yr, HR: 0.76 (0.55–1.06); OS < 65 yr, HR: 0.62 (0.44–0.86) |
KEYNOTE-189 (NCT02578680) [351] | 2018 | First line non squamous, cisplatin or carboplatin + pemetrexed + pembrolizumab versus cisplatin or carboplatin + pemetrexed | N = 616; median age = 64 yr; 65 years: 49% | OS ≥ 65 yr, HR: 0.64 (0.43–0.95); OS < 65 yr, HR: 0.43 (0.31–0.61) |
KEYNOTE-407 (NCT02775435) [352] | 2018 | First line squamous, carboplatin + paclitaxel + pembrolizumab | N = 559; median age = 65 yr; 65 years: 55% | OS ≥ 65 yr, HR: 0.74 (0.51–1.07); OS < 65 yr, HR: 0.52 (0.34–0.80) |
CheckMate 227 (NCT02477826) [353] | 2019 | First line, TPS > 1%, nivolumab + ipilimumab versus platinum-based chemotherapy | N = 1189; median age = 64 yr; 65 years: 49% | OS ≥ 75 yr, HR: 0.92 (0.57–1.48); OS 65–74 yr, HR: 0.91 (0.70–1.19); OS < 65 yr, HR: 0.70 (0.55–0.89) |
CheckMate 9LA (NCT03215706) [354] | 2021 | First line nivolumab + ipilimumab + platinum-based chemotherapy versus platinum-based chemotherapy | N = 719; median age = 65 yr; 65 years: 51% | OS ≥ 75 yr, HR: 1.21; OS 65–74 yr, HR: 0.62; OS < 65 yr, HR: 0.61 |
IMpower150 (NCT02366143) [355] | 2018 | First line or post-TKI non squamous carboplatin + paclitaxel + bevacizumab + atezolizumab versus carboplatin + paclitaxel + bevacizumab | N = 800; median age = 63 yr; 65 years: 45% | PFS ≥ 75 yr, HR: 0.78; PFS 65–74 yr, HR: 0.52; PFS < 65 yr, HR: 0.65 |
IMpower010 (NCT02486718) [356] | 2021 | resected IB-IIIA with chemotherapy followed by atezolizumab versus BSC | N = 1005; median age = 62 yr; 65 years: 67% | DFS ≥ 65 yr, HR: 0.76 (0.54–1.05); DFS < 65 yr, HR: 0.79 (0.61–1.03) |
Renal cell carcinoma | ||||
CheckMate 025 (NCT01668784) [357] | 2015 | Pretreated nivolumab versus everolimus | N = 821; median age = 62 yr; 65 years: 39% | OS ≥ 75 yr, HR: 1.23 (0.66–2.31); OS 65–74 yr, HR: 0.64 (0.45–0.91); OS < 65 yr, HR: 0.78 (0.60–1.01) |
CheckMate 214 (NCT02231749) [358] | 2018 | First line nivolumab + ipilimumab versus sunitinib | N = 1096; median age = 62 yr; 65 years: 38% | OS ≥ 75 yr, HR: 0.97 (0.48–1.95); OS 65–74 yr, HR: 0.86 (0.58–1.27); OS < 65 yr, HR: 0.53 (0.40–0.71) |
KEYNOTE-426 (NCT02853331) [359] | 2019 | First line pembrolizumab + axitinib versus sunitinib | N = 861; median age = 62 yr; 65 years: 38% | OS ≥ 65 yr, HR: 0.59 (0.36–0.97); OS < 65 yr, HR: 0.47 (0.30–0.73) |
JAVELIN 101 (NCT02684006) [360] | 2019 | First line avelumab + axitinib versus sunitinib | N = 886; median age = 61 yr; 65 years: 38% | PFS ≥ 65 yr, HR: 0.70 (0.49–0.99); PFS < 65 yr, HR: 0.68 (0.54–0.87) |
Urothelial carcinoma | ||||
KEYNOTE-045 (NCT02256436) [361] | 2017 | Pretreated pembrolizumab versus investigator choice chemotherapy | N = 542; median age = 66 yr; 65 years: 58% | OS ≥ 65 yr, HR: 0.76 (0.56–1.02); OS < 65 yr, HR: 0.75 (0.53–1.05) |
IMvigor-130 (NCT02807636) [362] | 2020 | First line platinum-based chemotherapy + atezolizumab versus platinum-based chemotherapy | N = 1231; median age = 68 yr; 65 years: 63% | PFS ≥ 65 yr, HR: 0.80 (0.66–0.97); PFS < 65 yr, HR: 0.82 (0.63–1.06) |
JAVELIN 100 (NCT02603432) [363] | 2020 | first line maintenance avelumab + BSC versus BSC | N = 700; median age = 69 yr; 65 years: 66% | OS ≥ 65 yr, HR: 0.63 (0.47–0.83); OS < 65 yr, HR: 0.79 (0.55–1.15) |