Enhancing Chemotherapy Efficacy in Pten -Deficient Prostate Tumors by Activating the Senescence-Associated Antitumor Immunity

Toso, Alberto; Revandkar, Ajinkya; Mitri, Diletta Di; Guccini, Ilaria; Proietti, Michele; Sarti, Manuela; Pinton, Sandra; Zhang, Jiangwen; Kalathur, Madhuri; Civenni, Gianluca; Jarrossay, David; Montani, Erica; Marini, Camilla; García-Escudero, Ramón; Scanziani, Eugenio; Grassi, Fabio; Pandolfi, Pier Paolo; Catapano, Carlo V.; Alimonti, Andrea

doi:10.1016/j.celrep.2014.08.044

Cited by 322 publications

(306 citation statements)

References 47 publications

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“…S6), cell types from two distinct lineages. This finding is consistent with the observation that JAK inhibitors can reprogram the SASP in senescent tumor cells, leading to improved antitumor immune responses (37).…”

Section: Discussionsupporting

confidence: 80%

“…A number of inhibitors that target different JAKs have been approved or are in phase I-III studies for treating myelofibrosis (23,(32)(33)(34), acute myeloid leukemia (23), lymphoma (23), and rheumatoid arthritis (23,35,36). JAK inhibitors recently have been found to reprogram the SASP in senescent tumor cells, contributing to improved antitumor response (37). Therefore, we investigated the role of the JAK pathway in age-related inflammation and dysfunction.…”

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confidence: 99%

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JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age

Tchkonia

Ding

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

564

479

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Chronic, low grade, sterile inflammation frequently accompanies aging and age-related diseases. Cellular senescence is associated with the production of proinflammatory chemokines, cytokines, and extracellular matrix (ECM) remodeling proteases, which comprise the senescence-associated secretory phenotype (SASP). We found a higher burden of senescent cells in adipose tissue with aging. Senescent human primary preadipocytes as well as human umbilical vein endothelial cells (HUVECs) developed a SASP that could be suppressed by targeting the JAK pathway using RNAi or JAK inhibitors. Conditioned medium (CM) from senescent human preadipocytes induced macrophage migration in vitro and inflammation in healthy adipose tissue and preadipocytes. When the senescent cells from which CM was derived had been treated with JAK inhibitors, the resulting CM was much less proinflammatory. The administration of JAK inhibitor to aged mice for 10 wk alleviated both adipose tissue and systemic inflammation and enhanced physical function. Our findings are consistent with a possible contribution of senescent cells and the SASP to age-related inflammation and frailty. We speculate that SASP inhibition by JAK inhibitors may contribute to alleviating frailty. Targeting the JAK pathway holds promise for treating age-related dysfunction.JAK/STAT pathway | cellular senescence | ruxolitinib | interleukin-6 | frailty

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Section: Discussionsupporting

confidence: 80%

mentioning

confidence: 99%

JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age

Tchkonia

Ding

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

564

479

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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Enhancement of cellular senescence in tumours triggers a stable cell growth arrest and activation of an antitumour immune response that can be exploited for cancer therapy. Currently, there are only a limited number of targeted therapies that act by increasing senescence in cancers, but the majority of them are not selective and also target healthy cells. Here we developed a chemogenomic screening to identify compounds that enhance senescence in PTEN-deficient cells without affecting normal cells. By using this approach, we identified casein kinase 2 (CK2) as a pro-senescent target. Mechanistically, we show that Pten loss increases CK2 levels by activating STAT3. CK2 upregulation in Pten null tumours affects the stability of Pml, an essential regulator of senescence. However, CK2 inhibition stabilizes Pml levels enhancing senescence in Pten null tumours. Taken together, our screening strategy has identified a novel STAT3-CK2-PML network that can be targeted for pro-senescence therapy for cancer.

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“…These data underscore the importance of optimally matching targeted therapy with chemotherapeutic agents. [118]. In addition, JAK2/STAT3 inhibition in mice bearing subcutaneous sarcomas that lack STAT3 activation modulates MDSC and dendritic cell proportions as well as their activity to reinstate anti-tumor immunity [119].…”

Section: Innate Immune Cellsmentioning

confidence: 99%

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

Coffelt

Visser

2015

Trends in Immunology

120

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SummaryConventional anti-cancer therapies, such as chemotherapy, radiotherapy and targeted therapy, are designed to kill cancer cells. Yet, the efficacy of anti-cancer therapies is not only determined by their direct effects on cancer cells, but also by off-target effects within the host immune system. Cytotoxic treatment regimens elicit a number of changes in immune-related parameters including the composition, phenotype and function of immune cells. In this review, we discuss the impact of innate and adaptive immune cells on the success of anti-cancer therapy, we examine the opportunities to exploit host immune responses to boost tumor clearing and we highlight the challenges facing the treatment of advanced metastatic disease. Then and now: The link between the immune system and anti-cancer therapiesThe relationship between anti-cancer therapies and the immune system is as old as the invention of anti-cancer therapies themselves. After the use of mustard gas in the trenches of World War I, a seminal observation was made that some exposed soldiers displayed severe loss of bone marrow and lymph node cells [1]. This observation then spurred the idea that the anti-proliferative capacity of mustard gas may also slow the growth of cancer cells.Experiments carried out in mice transplanted with lymphoid tumors were convincing enough to treat a lymphoma patient [2], and these events initiated the standardized treatment of cancer patients with chemotherapy [3,4].Fast forward 100 years later. The influence of immune cells on tumor progression and metastasis is well established [5], and an appreciation for the immune system's impact during conventional anti-cancer therapy treatment is growing. Recent seminal advances indicate that immune cells can shape the outcome of various anti-cancer therapies. As such, 2 immune cells and their molecular mediators have evolved into bona vide targets of therapeutic manipulation in cancer patients. The recent breakthrough of immunotherapeutics that inhibit negative immune regulatory pathways, such as anti-CTLA4 and anti-PD1, has initiated a new era in the treatment of cancer [6]. In parallel, immunomodulatory strategies aimed at dampening pro-tumor functions of immune cells are currently being tested in cancer patients [7]. Immune cells also function as reliable biomarkers, since their abundance or activation status often predicts how well patients respond to a particular treatment regimen.Here, we review these novel experimental and clinical insights, highlighting potential implications for the development of synergistic therapies designed to combat primary tumors and, more importantly, metastatic disease. The pros and cons of experimental mouse modelsResearch questions aimed at understanding the role of immune cells during anti-cancer therapy require models that mirror the complex interactions between the immune system and diverse forms of human cancers. Transplantable cancer cell line models and carcinogeninduced cancer models are the most frequently used for these purposes. However...

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Enhancing Chemotherapy Efficacy in Pten -Deficient Prostate Tumors by Activating the Senescence-Associated Antitumor Immunity

Cited by 322 publications

References 47 publications

JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age

JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age

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

Immune-mediated mechanisms influencing the efficacy of anticancer therapies

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