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Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer
Diletta Di Mitri1, Alberto Toso1, Jing Jing Chen2
11] Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona CH6500, Switzerland [2].
Abstract:
Aberrant activation of oncogenes or loss of tumour suppressor genes opposes malignant transformation by triggering a stable arrest in cell growth, which is termed cellular senescence. This process is finely tuned by both cell-autonomous and non-cell-autonomous mechanisms that regulate the entry of tumour cells to senescence. Whether tumour-infiltrating immune cells can oppose senescence is unknown. Here we show that at the onset of senescence, PTEN null prostate tumours in mice are massively infiltrated by a population of CD11b(+)Gr-1(+) myeloid cells that protect a fraction of proliferating tumour cells from senescence, thus sustaining tumour growth. Mechanistically, we found that Gr-1(+) cells antagonize senescence in a paracrine manner by interfering with the senescence-associated secretory phenotype of the tumour through the secretion of interleukin-1 receptor antagonist (IL-1RA). Strikingly, Pten-loss-induced cellular senescence was enhanced in vivo when Il1ra knockout myeloid cells were adoptively transferred to PTEN null mice. Therapeutically, docetaxel-induced senescence and efficacy were higher in PTEN null tumours when the percentage of tumour-infiltrating CD11b(+)Gr-1(+) myeloid cells was reduced using an antagonist of CXC chemokine receptor 2 (CXCR2). Taken together, our findings identify a novel non-cell-autonomous network, established by innate immunity, that controls senescence evasion and chemoresistance. Targeting this network provides novel opportunities for cancer therapy.
Insights
Tumor-infiltrating myeloid cells protect cancer cells from senescence by secreting IL-1RA. Inhibiting these cells enhances anti-cancer therapies like docetaxel, offering new cancer treatment strategies.
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- Cellular senescence, a stable cell growth arrest, normally opposes malignant transformation.
- Both cell-intrinsic and extrinsic factors regulate tumor cell entry into senescence.
- The role of tumor-infiltrating immune cells in modulating senescence remains unclear.
Purpose of the Study:
- To investigate the role of tumor-infiltrating immune cells in regulating cellular senescence in prostate tumors.
- To elucidate the mechanisms by which immune cells might influence senescence evasion.
- To explore therapeutic strategies targeting immune-mediated senescence evasion.
Main Methods:
- Analysis of PTEN-null prostate tumors in mice for immune cell infiltration and senescence.
- Investigated the mechanism of senescence antagonism by CD11b(+)Gr-1(+) myeloid cells.
- Utilized interleukin-1 receptor antagonist (IL-1RA) knockout and CXCR2 antagonist in therapeutic models.
Main Results:
- PTEN-null prostate tumors showed massive infiltration of CD11b(+)Gr-1(+) myeloid cells at the onset of senescence.
- These myeloid cells secreted IL-1RA, antagonizing tumor cell senescence in a paracrine manner.
- Depletion of these myeloid cells or IL-1RA enhanced Pten-loss-induced senescence; CXCR2 inhibition improved docetaxel efficacy.
Conclusions:
- Innate immune cells, specifically myeloid cells secreting IL-1RA, promote senescence evasion in tumors.
- This non-cell-autonomous network sustains tumor growth and contributes to chemoresistance.
- Targeting this immune-mediated senescence evasion network presents a promising avenue for cancer therapy.
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