Institute of Research in Oncology, Bellinzona, Switzerland
Robust scientific evidence demonstrates that senescence induction in cancer works as a potent weapon to eradicate tumorigenesis. Therapies that enhance senescence not only promote a stable cell growth arrest but also work as a strong stimulus for the activation of the antitumour immune response. However, recent advances suggest that if senescent tumour cells are not cleared from the tumours, they may promote tumour progression and metastasis. In this article, we focus on concepts that are relevant to a pro-senescence therapeutic approach, including caveats, and we propose therapeutic strategies that involve the combined use of pro-senescence therapies with immunotherapies to promote the clearance of senescent tumour cells. In our opinion, these approaches may avoid potential negative effects of pro-senescence therapies and may also enhance the efficacy of currently available immunotherapies.
Keywords: senescence, cell autonomous regulation of senescence in cancer, SASP, non-cell autonomous regulation of senescence in cancer, pro-senescence therapy for cancer, SASP reprogramming, immune cell subsets, myeloid-derived suppressor cells
Senescence is a stable cell cycle arrest that limits the proliferative lifespan of human diploid cells, thereby promoting a gradual deterioration of the human body. In culture, normal cells can reach a maximum of 50 cell divisions before becoming senescent. This phenomenon, known as the “Hayflick limit”, occurs as a result of progressive shortening of telomeres upon each cell division [1, 2]. In contrast to normal cells, one of the hallmarks of cancer cells is the capability to escape senescence, thus acquiring a limitless replicative potential that is the prelude to invasion, metastasis and additional features of malignancy . However, cancer cells can undergo senescence if subjected to certain insults such as oncogenic stress, DNA damage and metabolic changes. This type of senescence response occurs immediately and also independently of telomere shortening, a phenomenon known as “premature” senescence [2, 4]. For instance, several anticancer chemotherapies and radiotherapies are known to induce senescence in both normal and cancer cells . Similarly, changes in culture conditions that are associated with metabolic stress are also known to induce senescence .
In 2005, four papers reported that senescence can also occur in tumour cells in vivo as a consequence of overexpression of oncogenes or loss of tumour suppressor genes, demonstrating for the first time that senescence acts as a barrier against tumorigenesis [7–10]. Analysis of tumour samples from patients affected by prostate tumours, nevi or indolent lymphomas demonstrated that, whereas benign tumours accumulate markers of senescence, invasive cancers lack senescence [7–10]. Subsequent publications validated these findings in different types of tumour [11, 12].
Given the surprising discovery that senescence limits the development of cancer, we and others envisioned targeted therapies that selectively enhanced senescence in cancer cells used for the therapy of various tumours. This approach, named “pro-senescence” therapy for cancer, differs from the chemotherapy-induced senescence that affects both normal and cancer cells .
Pro-senescence therapy for cancer: a current challenge?
Several small molecule inhibitors that are currently in clinical development have been reported to induce senescence in cancer [9, 13, 14]. Among these compounds, inhibitors of the cyclin-dependent kinases CDK4/6 have been associated with a high percentage of responses in patients affected by breast cancer and are the most promising pro-senescence compounds currently being tested in the clinic . These compounds promote cellular senescence by decreasing the phosphorylation of retinoblastoma protein (RB), thereby activating E2F transcription factors .
Compounds that enhance the level of the tumour suppressor gene p53, such as MDM2 (mouse double minute 2 homolog) inhibitors and PRIMA-1 (proline-rich membrane anchor 1) analogues, have been reported to enhance senescence in tumour cells with normal and mutant p53 and are currently being tested in the clinic for the treatment of haematological and solid tumours [16–18]. Adenoviral delivery of p53, in tumour cells lacking this tumour suppressor gene, also triggers senescence . Gendicine and H101, two p53-adenoviral vectors, have been approved in China in combination with chemotherapy for the treatment of head and neck squamous cell carcinoma. However, these vectors are not widely used for patients around the world . Another compound that enhances senescence by controlling p53 is dasatinib, an Src and c-Kit kinase inhibitor currently available for use in the clinic . Imetelstat, which is an inhibitor of telomerase activity and controls telomere shortening, has also been shown to be associated with senescence activation in cancer cells . Imetelstat has been recently shown to be effective in patients affected by myelofibrosis and essential thrombocytopenia . Finally, our group has recently demonstrated that an antagonist of the type 2 C-X-C chemokine receptor (CXCR2) can enhance senescence in prostate cancers by blocking the recruitment of tumour infiltrating myeloid cells . Clinical trials are ongoing to assess the efficacy of these compounds in patients affected by different tumours.
Many compounds that are currently being tested at the preclinical level are also promising pro-senescence therapies. Inhibitors of SirT1, a protein deacetylase that negatively regulates p53 function in cancer, induced senescence in preclinical tumour models . MYC inhibitors can also drive a cellular senescence response . The use of small molecules such as 10058-F4 derivatives  and RNA interference (RNAi) technologies [27, 28] provides strategies to target MYC for cancer therapy and are currently being tested at the preclinical level. Intriguingly, BET (bromodomain and extra-terminal motif) protein bromodomain inhibitors, such as JQ1, suppress MYC transcription, thereby enhancing senescence, and are a promising class of compounds currently in clinical trials in different cancer patients [29, 30]. From a therapeutic point of view, a current challenge for the development of optimal pro-senescence therapies is to identify compounds that activate senescence in advanced tumour cells without affecting normal cells. Preclinical evidence demonstrates that Skp2 (S-phase kinase-associated protein 2) inhibitors drive senescence in advanced p53 null prostate cancer by upregulating p27 without affecting normal cells . Unpublished observations from our group demonstrates that a γ-secretase inhibitor elicits senescence in Pten;p53 double null prostate cancers by also enhancing p27 levels. Similarly, casein kinase 2 (CK2) inhibitors enhance senescence in phosphatase and tensin homolog (PTEN)-deficient breast and prostate cancer cells, whereas normal cells and wild-type PTEN tumour cells remain unaffected . In MYC overexpressing lymphoma tumours, pharmacological inhibition of CDK2 induces senescence in tumour cells driven by MYC overexpression without affecting normal cells .
Taken together, these findings demonstrate that several compounds are capable of enhancing senescence in cancer and that cancer cell-selective induction of senescence represents a strong antitumour response.
Another challenge in the field of senescence therapy for cancer is the lack of clinically validated biomarkers for the identification of senescence in human tumours . The prognostic use of senescence-associated-β-galactosidase (SA-β-galactosidase), a well characterised in vitro marker for senescence, has been tested in small trials evaluating the efficacy of neo-adjuvant chemotherapies [34, 35]. Results from these trials demonstrate that this marker increases upon treatment and predicts patient outcome. However, the use of SA-β-galactosidase alone as a unique marker of senescence has been criticised since it can lead to many false positives. Recent findings have identified of new markers of senescence with prognostic relevance [34, 36]. However, neither SA-β-galactosidase staining nor additional markers have been used so far in large clinical trials to evaluate the efficacy of pro-senescence compounds such as CDK4/6, MDM2 inhibitors or imetelstat. Thus, development of novel biomarkers that can accurately assess the occurrence of senescence in cancer patients is the need of the hour. This would help improve the stratification of patients who may respond to therapies that enhance senescence in cancer.
Non-cell autonomous regulation of senescence in cancer
Senescent tumour cells remain stably arrested, but are also metabolically active and communicate with the surrounding tumour microenvironment. Indeed, in contrast to apoptotic cells, senescent cells secrete a number of growth factors, cytokines and proteases that impact on the tumour microenvironment. These secreted proteins constitute the so-called senescence-associated secretory phenotype (SASP). SASP components include inflammatory and immune-modulatory cytokines (e.g. interleukins 6 and 8: IL6 and IL8), growth factors (e.g. insulin-like growth factor-binding proteins: IGFBPs), cell surface molecules (e.g. tumour necrosis factor [TNF] receptors) and survival factors. The SASP can reinforce the senescence programme and influence the tumour microenvironment, impacting on the stroma and on the tumour immune cells [37, 38]. These effects can be either positive or negative, a phenomenon that has been described as the “double-edged sword” of the SASP . For instance, IL8 and IL6, secreted by senescence cells, are needed for the induction and maintenance of senescence. IL8 is a known activator of the innate immune response through its binding to CXCR1 and CXCR2, and inhibition of CXCR2 promotes senescence bypass in oncogene-induced senescence (OIS) [40, 41]. Inhibition of IL6 or IL6 receptors also promotes senescence evasion in OIS . In addition, recent evidence demonstrates that senescent cells can transmit senescence to normal and tumour cells by releasing IL1α. This phenomenon, called “paracrine” senescence, contributes to the tumour suppressive function of senescence in cancer  (fig. 1A). Moreover, senescent tumour cells have been described to promote through their SASP both the recruitment and activation of several immune subsets of the innate and adaptive tumour immune responses, including M1-like macrophages, natural killer (NK) cells, and T-helper 1 (Th1) lymphocytes. Such immune-infiltrates can restrain tumour progression by mediating the clearance of senescent tumour cells [44, 45]. Senescence cells can also promote the generation of an antigen-specific immune-surveillance against themselves . Finally, recent findings demonstrate that Th1 lymphocytes are also capable of promoting senescence in tumour cells through the secretion of interferon-γ (IFN-γ) and TNF-α. Such cytokine-induced senescence strictly requires STAT1 (signal transducer and activator of transcription 1) and TNF receptor-1 signalling in addition to p16 INK4A . Therefore, senescent tumour cells can, in principle, recruit T cells that can, in turn, propagate senescence in nonsenescent cells and mediate tumour clearance (fig. 1B). Macrophages secreting transforming growth factor-β (TGF-β) have also been reported to induce senescence in cancer  (fig. 1B).
Paradoxically, senescence trough the SASP can also promote tumorigenesis by supporting the proliferation of neighbouring tumour cells and increasing tumour vascularisation . IL8 and IL6 secreted by senescence cells can promote tumorigenesis, acting in a paracrine manner [42, 49]. TGF-β and IL1 secreted by senescent cells have been found to cooperatively support tumorigenesis through activation of the JAK/STAT, TGFβ/SMAD and IL1/NF-κB signalling pathways . CXCL1 secreted by senescent fibroblasts can stimulate the growth of premalignant and malignant mammary epithelial cells . Furthermore, matrix metalloproteinases (MMPs) secreted by senescent cells enhance the tumorigenicity of breast epithelial cells in xenografts models . In addition, the SASP can hinder chemotherapy efficacy by inducing the activation of STAT3 in tumour cells . Thus, factors secreted by senescent cells can exert both autocrine and paracrine effects, which can be either positive or negative (fig. 1A). Therefore, if senescent tumour cells are not removed from the tumours by the tumour immune response, the persistent stimulation of the SASP can promote cell proliferation, angiogenesis and epithelial–mesenchymal transition, thereby sustaining cancer progression .
Additional examples of non-cell autonomous regulation of senescence in cancer include sterile inflammation and the gut microbiota. Intriguingly, factors released by damaged tumour cells during sterile inflammation can promote senescence evasion in early tumour lesions through an unidentified mechanism . Finally, metabolites secreted by the gut microbiota can promote senescence evasion and liver tumorigenesis . These data demonstrate that senescence can be regulated in a non-cell autonomous manner at different levels, and by different factors.
SASP reprogramming as therapeutic strategy to enhance the tumour-suppressive power of senescence therapies
As discussed above, SASP has profound effects on the surrounding tumour microenvironment and it represents a promising target for cancer therapy. Several groups have recently proposed therapies that reprogram the SASP to enhance the tumour-suppressive role of senescence in cancer and restrain the negative effects of the SASP. For instance, we have recently shown that Stat3 regulates the SASP of Pten-loss induced cellular senescence (PICS). In Pten null senescent tumours, Stat3 activation promotes an immunosuppressive tumour microenvironment that impairs senescence surveillance. However, pharmacological inhibition of Janus kinase 2 (JAK2) in these tumours induces the reprogramming of the SASP, thus leading to an antitumour immune response that promotes the clearance of senescence tumour cells . The SASP is also controlled by mTOR (mechanistic target of rapamycin). Indeed, mTOR inhibitors reduced SASP by differentially regulating the translation of the MAP kinase-activated protein kinase MK2 through 4EBP1 (eukaryotic translation initiation factor 4E-binding protein 1) . Although mTOR inhibition prevented the pro-tumorigenic effects of the SASP in vivo, it also interfered with the induction of paracrine senescence and senescence surveillance, two important tumour suppressive arms of senescence . In another study, rapamycin, a well-known mTOR inhibitor, also suppressed the ability of senescent fibroblasts to stimulate prostate tumour growth in mice by attenuating the SASP . Therefore, JAK2 and mTOR inhibitors could be used in the clinic to decrease some of the negative effects of the SASP in tumours with therapy-induced senescence. The SASP is also regulated by BRD4, one of the bromodomain and extra-terminal motif (BET) proteins. Inhibition of BRD4 by JQ1 blocked the SASP in a model of OIS, thereby affecting senescence surveillance in vivo . Therefore, although previous evidence demonstrated that JQ1 induces senescence in cancer [29, 30], it also affects the removal of senescence cells from tumours and should be combined with compounds that reactivate senescence surveillance or that selectively kill senescence tumour cells (senolytic therapy). Simvastatin, a hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor known to attenuate inflammation, has also been recently identified as a modulator of the SASP. Interestingly, in vitro evidence demonstrates that simvastatin suppresses breast cancer cell proliferation induced by senescent cells . Altogether, these studies highlight the importance of strategies aiming at the SASP reprogramming as potential cancer therapies. Thus, identification of compounds that can attenuate the “dark side” of the SASP without affecting its tumour suppressive function could be used in the clinic to enhance the therapeutic efficacy of pro-senescence compounds.
Manipulation of the tumour immune response for pro-senescence therapy for cancer
Recent evidence from our laboratory demonstrates that tumour-infiltrating myeloid cells promote prostate tumour progression by opposing senescence in vivo . In another paper, we have also demonstrated that these Gr1+ myeloid cells are myeloid-derived suppressor cells (MDSCs) because they suppress the recruitment and activation of T cells . MDSCs are a phenotypically heterogeneous cell population that has common biological activity. Cancer formation promotes the migration of MDSCs from the bone marrow to the tumour through the release of several soluble factors that induce myeloid cells trafficking, proliferation, and differentiation . MDSCs mediate senescence evasion in cancer cells through the secretion of IL1 receptor antagonist (IL1RA) into the tumour microenvironment. Indeed, IL1RA blocks the IL1R signalling that is required for PICS. Interestingly, patients with high IL1RA tumour levels did not respond to chemotherapy-induced senescence (docetaxel) and showed a short disease-free survival compared with patients with normal IL1RA levels. Taken together these findings demonstrate that senescence in cancer can be antagonised in a non-cell-autonomous manner by a subset of tumour-infiltrating immune cells. Importantly, we have also shown that treatment with CXCR2 antagonists potentiates senescence by inhibiting MDSC recruitment .
An intriguing aspect of the role of MDSCs in cancer is that these cells also have prognostic relevance in cancer patients and affect tumorigenesis not only by blocking senescence but also by additional mechanisms . Several studies demonstrate that the number of circulating MDSCs correlate with poor prognosis in patients affected by head and neck, melanoma, breast, lung and prostate cancers [62–64]. MDSCs, together with regulatory T cells (Tregs) and tumour-associated macrophages, are the main immune subsets responsible for immunosuppression in the tumour microenvironment. Their suppressive activity is mediated by a variety of mechanisms, mostly involving arginase, inducible nitric oxide synthase (iNOS), reactive oxygen species, TGF-β, IL10, and prostaglandin E2. This suppressive activity results in tolerance to cytotxic T lymphocytes (CTLs), which thus lose their effector function at the tumour site [61, 65].
In addition, MDSCs are also involved in a whole array of nonimmunological functions, such as the promotion of angiogenesis, tumour local invasion and metastases. Indeed, MDSCs produce MMPs that can support tumour cell invasion by directly promoting tumour angiogenesis and lymphangiogenesis [66–69]. Several chemotherapies can suppress the MDSC count and it is postulated that this may be critical to benefit from such treatments [70, 71]. However, following anticancer treatments, the frequency of MDSCs does not decline to the level seen in tumour-free mice and healthy human subjects. Moreover, tumour recurrence after several treatments correlates with re-expansion of MDSCs . Therefore, treatments that decrease the trafficking or function of myeloid cells in the tumours may not only enhance the efficacy of pro-senescence therapies but also limit the additional pro-tumorigenic features of MDSCs. Thus, our findings have paved the way for the development of treatments that combine different immunotherapies with pro-senescence compounds, and novel trials are ongoing to validate the relevance of these findings in patients affected by various tumours.
Dual targeting of senescence and the tumour immune response for cancer therapy
Accumulating experimental evidence lends weight to the concept that both cell-autonomous and non-cell-autonomous mechanisms can account for senescence evasion. Consequently, treatments that elicit senescence induction or inhibit senescence evasion in tumours are fundamental to limiting tumour progression. As discussed above, a plethora of pro-senescence compounds with different specificities are currently under evaluation in the clinic. A step forward will be to devise multiple targeted therapies that simultaneously or subsequently target senescence tumour cells and the tumour microenvironment. Because cellular senescence has been associated with the activation of anti-tumour mechanisms, mainly mediated by the SASP and the tumour immune response , it is reasonable to hypothesise that the combination with immunotherapy approaches would be the most effective (fig. 1C). A recent report demonstrates that T-cell-activating therapies based on CD137 antibodies enhance the efficacy of pro-senescence compounds in a xenograft model of melanoma . Recent advances in immunotherapy for cancer involve the clinical use of immune checkpoint inhibitors. These therapies have improved the median survival and long-term durable responses of patients affected by various tumours . However, the long-term clinical benefit is limited in a number of patients. This further highlights the importance of combined therapies to improve the survival of treated patients. We believed that pro-senescence therapies might be introduced into the clinic also as an adjuvant regimen to increase the efficacy of immune checkpoint inhibitors. However, preclinical evidence is still needed to support such a claim, and trials are currently ongoing in different laboratories to validate this hypothesis.
The use of senolytic therapies may also enhance the efficacy of pro-senescence therapies by removing senescence cells from the tumour . Senolytic therapies may be administered concomitantly with or after pro-senescence compounds to decrease potential negative side effects of the SASP in tumours where the tumour immune clearance does not take place. As recently reported, senescent tumour cells rely on pro-survival networks and are therefore more susceptible to the inhibition of these pathways. For instance, Bcl-2/Bcl-x inhibitors may be used in combination with pro-senescence compounds to enhance the efficacy of pro-senescence therapy . Since senescent tumour cells also undergo to metabolic reprogramming, pharmacological inhibition of specific metabolic demands may be used to promote the clearance of senescent cells in tumours treated with pro-senescence therapies. Such an approach has been successfully tested in a model of lymphoma but it still remains to be validated in additional tumour models . In conclusion, we believe that pro-senescence therapy for cancer is a promising new therapeutic strategy and that in the future novel, therapies based on senescence induction in cancer will be the standard of care for the treatment of cancer patients.
No financial support and no other potential conflict of interest relevant to this article was reported.
Correspondence: Andrea Alimonti, Istituto Oncologico della Svizzera Italiana, Via Vincenzo Vela, 6, CH-6500 Bellinzona, andrea.alimonti[at]ior.iosi.ch
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