Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer

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.

Neutrophils in cancer: neutral no more

“…For example, depletion of Gr1 + myeloid cells or Ly6G + neutrophils reduced the anti-cancer efficacy of cyclophosphamide and doxorubicin in tumor inoculation models 187,188 . These data contrast to the improved tumor inhibition achieved by combining CXCR2 blockade with doxorubicin, cyclophosphamide or docetaxel in xenograft and de novo tumorigenesis mouse models 58,132 . Moreover, some chemotherapeutics, such as gemcitabine and 5-fluorouracil, directly reduce the viability and/or change the functionality of myeloid cells, which then influences the anti-cancer efficacy of these drugs.…”

A chemogenomic screening identifies CK2 as a target for pro-senescence therapy in PTEN-deficient tumours

“…1a). As previously reported, upon inactivation of Pten, 30% of the cells undergo senescence whereas the remaining 70% of Pten À / À cells bypass this arrest and continue to proliferate 7 (Supplementary Methods). This provides a screening window to identify compounds that enhance senescence by further decreasing proliferation of Pten À / À cells, as previously demonstrated for Nutlin-3, a MDM2 inhibitor 1 .…”

“…Our screening approach coupling a small-molecule screening with a shRNA screen has allowed us to focus on a target that has been identified in both the screens, using complementary methodologies. Given that the tumour immune response is an essential component of the tumour suppressive function of senescence in cancer, these compounds could be tested in the clinic either alone or in combination with compounds that activate the tumour immune response or reprogramme the senescence-associated secretory phenotype as recently demonstrated from our group 7,42 . In this respect, we envisioned that our screening platform may also be implemented with different immune assays.…”

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

“…Similarly, docetaxel synergizes with a CXCR2 inhibitor to prevent tumor progression in a GEMM for Ptendeficient prostate cancer [45]. In these prostate tumors, infiltrating neutrophils secrete IL1RA to counteract cancer cell senescence and activate proliferation.…”