Skip to main navigation menu Skip to main content Skip to site footer
##common.pageHeaderLogo.altText##

Review article: Biomedical intelligence

Vol. 147 No. 0304 (2017)

Aging tumour cells to cure cancer: “pro-senescence” therapy for cancer

  • Arianna Calcinotto
  • Andrea Alimonti
DOI
https://doi.org/10.57187/smw.2017.14367
Cite this as:
Swiss Med Wkly. 2017;147:w14367
Published
17.01.2017

Summary

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.

References

  1. Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961;25(3):585–621. doi:.https://doi.org/10.1016/0014-4827(61)90192-6 DOI: https://doi.org/10.1016/0014-4827(61)90192-6
  2. Courtois-Cox S, Jones SL, Cichowski K. Many roads lead to oncogene-induced senescence. Oncogene. 2008;27(20):2801–9. doi:.https://doi.org/10.1038/sj.onc.1210950 DOI: https://doi.org/10.1038/sj.onc.1210950
  3. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74. doi:.https://doi.org/10.1016/j.cell.2011.02.013 DOI: https://doi.org/10.1016/j.cell.2011.02.013
  4. d’Adda di Fagagna F. Living on a break: cellular senescence as a DNA-damage response. Nat Rev Cancer. 2008;8(7):512–22. doi:.https://doi.org/10.1038/nrc2440 DOI: https://doi.org/10.1038/nrc2440
  5. Ewald JA, Desotelle JA, Wilding G, Jarrard DF. Therapy-induced senescence in cancer. J Natl Cancer Inst. 2010;102(20):1536–46. doi:.https://doi.org/10.1093/jnci/djq364 DOI: https://doi.org/10.1093/jnci/djq364
  6. Sherr CJ, DePinho RA. Cellular senescence: mitotic clock or culture shock? Cell. 2000;102(4):407–10. doi:.https://doi.org/10.1016/S0092-8674(00)00046-5 DOI: https://doi.org/10.1016/S0092-8674(00)00046-5
  7. Braig M, Lee S, Loddenkemper C, Rudolph C, Peters AH, Schlegelberger B, et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature. 2005;436(7051):660–5. doi:.https://doi.org/10.1038/nature03841 DOI: https://doi.org/10.1038/nature03841
  8. Chen Z, Trotman LC, Shaffer D, Lin HK, Dotan ZA, Niki M, et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature. 2005;436(7051):725–30. doi:.https://doi.org/10.1038/nature03918 DOI: https://doi.org/10.1038/nature03918
  9. Collado M, Gil J, Efeyan A, Guerra C, Schuhmacher AJ, Barradas M, et al. Tumour biology: senescence in premalignant tumours. Nature. 2005;436(7051):642. doi:.https://doi.org/10.1038/436642a DOI: https://doi.org/10.1038/436642a
  10. Michaloglou C, Vredeveld LC, Soengas MS, Denoyelle C, Kuilman T, van der Horst CM, et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature. 2005;436(7051):720–4. doi:.https://doi.org/10.1038/nature03890 DOI: https://doi.org/10.1038/nature03890
  11. Courtois-Cox S, Genther Williams SM, Reczek EE, Johnson BW, McGillicuddy LT, Johannessen CM, et al. A negative feedback signaling network underlies oncogene-induced senescence. Cancer Cell. 2006;10(6):459–72. doi:.https://doi.org/10.1016/j.ccr.2006.10.003 DOI: https://doi.org/10.1016/j.ccr.2006.10.003
  12. Gewinner C, Wang ZC, Richardson A, Teruya-Feldstein J, Etemadmoghadam D, Bowtell D, et al. Evidence that inositol polyphosphate 4-phosphatase type II is a tumor suppressor that inhibits PI3K signaling. Cancer Cell. 2009;16(2):115–25. doi:.https://doi.org/10.1016/j.ccr.2009.06.006 DOI: https://doi.org/10.1016/j.ccr.2009.06.006
  13. Nardella C, Clohessy JG, Alimonti A, Pandolfi PP. Pro-senescence therapy for cancer treatment. Nat Rev Cancer. 2011;11(7):503–11. doi:.https://doi.org/10.1038/nrc3057 DOI: https://doi.org/10.1038/nrc3057
  14. Kalathur M, Toso A, Chen J, Revandkar A, Danzer-Baltzer C, Guccini I, et al. A chemogenomic screening identifies CK2 as a target for pro-senescence therapy in PTEN-deficient tumours. Nat Commun. 2015;6:7227. doi:.https://doi.org/10.1038/ncomms8227 DOI: https://doi.org/10.1038/ncomms8227
  15. O’Leary B, Finn RS, Turner NC. Treating cancer with selective CDK4/6 inhibitors. Nat Rev Clin Oncol. 2016;13(7):417–30. doi:.https://doi.org/10.1038/nrclinonc.2016.26 DOI: https://doi.org/10.1038/nrclinonc.2016.26
  16. Wade M, Li YC, Wahl GM. MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer. 2013;13(2):83–96. doi:.https://doi.org/10.1038/nrc3430 DOI: https://doi.org/10.1038/nrc3430
  17. Peng X, Zhang MQ, Conserva F, Hosny G, Selivanova G, Bykov VJ, et al. APR-246/PRIMA-1MET inhibits thioredoxin reductase 1 and converts the enzyme to a dedicated NADPH oxidase. Cell Death Dis. 2013;4(10):e881. doi:.https://doi.org/10.1038/cddis.2013.417 DOI: https://doi.org/10.1038/cddis.2013.417
  18. Bykov VJ, Issaeva N, Selivanova G, Wiman KG. Mutant p53-dependent growth suppression distinguishes PRIMA-1 from known anticancer drugs: a statistical analysis of information in the National Cancer Institute database. Carcinogenesis. 2002;23(12):2011–8. doi:.https://doi.org/10.1093/carcin/23.12.2011 DOI: https://doi.org/10.1093/carcin/23.12.2011
  19. Shi J, Zheng D. An update on gene therapy in China. Curr Opin Mol Ther. 2009;11(5):547–53.
  20. Chen GX, Zhang S, He XH, Liu SY, Ma C, Zou XP. Clinical utility of recombinant adenoviral human p53 gene therapy: current perspectives. Onco Targets Ther. 2014;7:1901–9. doi:.https://doi.org/10.2147/OTT.S50483 DOI: https://doi.org/10.2147/OTT.S50483
  21. Dos Santos C, McDonald T, Ho YW, Liu H, Lin A, Forman SJ, et al. The Src and c-Kit kinase inhibitor dasatinib enhances p53-mediated targeting of human acute myeloid leukemia stem cells by chemotherapeutic agents. Blood. 2013;122(11):1900–13. doi:.https://doi.org/10.1182/blood-2012-11-466425 DOI: https://doi.org/10.1182/blood-2012-11-466425
  22. Tefferi A, Lasho TL, Begna KH, Patnaik MM, Zblewski DL, Finke CM, et al. A Pilot Study of the Telomerase Inhibitor Imetelstat for Myelofibrosis. N Engl J Med. 2015;373(10):908–19. doi:.https://doi.org/10.1056/NEJMoa1310523 DOI: https://doi.org/10.1056/NEJMoa1310523
  23. Di Mitri D, Toso A, Chen JJ, Sarti M, Pinton S, Jost TR, et al. Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer. Nature. 2014;515(7525):134–7. doi:.https://doi.org/10.1038/nature13638 DOI: https://doi.org/10.1038/nature13638
  24. van Leeuwen I, Lain S. Sirtuins and p53. Adv Cancer Res. 2009;102:171–95. doi:.https://doi.org/10.1016/S0065-230X(09)02005-3 DOI: https://doi.org/10.1016/S0065-230X(09)02005-3
  25. Yetil A, Anchang B, Gouw AM, Adam SJ, Zabuawala T, Parameswaran R, et al. p19ARF is a critical mediator of both cellular senescence and an innate immune response associated with MYC inactivation in mouse model of acute leukemia. Oncotarget. 2015;6(6):3563–77. doi:.https://doi.org/10.18632/oncotarget.2969 DOI: https://doi.org/10.18632/oncotarget.2969
  26. Huang MJ, Cheng YC, Liu CR, Lin S, Liu HE. A small-molecule c-Myc inhibitor, 10058-F4, induces cell-cycle arrest, apoptosis, and myeloid differentiation of human acute myeloid leukemia. Exp Hematol. 2006;34(11):1480–9. doi:.https://doi.org/10.1016/j.exphem.2006.06.019 DOI: https://doi.org/10.1016/j.exphem.2006.06.019
  27. Pastorino F, Brignole C, Marimpietri D, Di Paolo D, Zancolli M, Pagnan G, et al. Targeted delivery of oncogene-selective antisense oligonucleotides in neuroectodermal tumors: therapeutic implications. Ann N Y Acad Sci. 2004;1028(1):90–103. doi:.https://doi.org/10.1196/annals.1322.010 DOI: https://doi.org/10.1196/annals.1322.010
  28. Civenni G, Malek A, Albino D, Garcia-Escudero R, Napoli S, Di Marco S, et al. RNAi-mediated silencing of Myc transcription inhibits stem-like cell maintenance and tumorigenicity in prostate cancer. Cancer Res. 2013;73(22):6816–27. doi:.https://doi.org/10.1158/0008-5472.CAN-13-0615 DOI: https://doi.org/10.1158/0008-5472.CAN-13-0615
  29. Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146(6):904–17. doi:.https://doi.org/10.1016/j.cell.2011.08.017 DOI: https://doi.org/10.1016/j.cell.2011.08.017
  30. Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, et al. Selective inhibition of BET bromodomains. Nature. 2010;468(7327):1067–73. doi:.https://doi.org/10.1038/nature09504 DOI: https://doi.org/10.1038/nature09504
  31. Lin HK, Chen Z, Wang G, Nardella C, Lee SW, Chan CH, et al. Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence. Nature. 2010;464(7287):374–9. doi:.https://doi.org/10.1038/nature08815 DOI: https://doi.org/10.1038/nature08815
  32. Campaner S, Doni M, Hydbring P, Verrecchia A, Bianchi L, Sardella D, et al. Cdk2 suppresses cellular senescence induced by the c-myc oncogene. Nat Cell Biol. 2010;12(1):54–9, 1–14. doi:.https://doi.org/10.1038/ncb2004 DOI: https://doi.org/10.1038/ncb2004
  33. Althubiti M, Lezina L, Carrera S, Jukes-Jones R, Giblett SM, Antonov A, et al. Characterization of novel markers of senescence and their prognostic potential in cancer. Cell Death Dis. 2014;5(11):e1528. doi:.https://doi.org/10.1038/cddis.2014.489 DOI: https://doi.org/10.1038/cddis.2014.489
  34. te Poele RH, Okorokov AL, Jardine L, Cummings J, Joel SP. DNA damage is able to induce senescence in tumor cells in vitro and in vivo. Cancer Res. 2002;62(6):1876–83.
  35. Itahana K, Campisi J, Dimri GP. Methods to detect biomarkers of cellular senescence: the senescence-associated beta-galactosidase assay. Methods Mol Biol. 2007;371:21–31. doi:.https://doi.org/10.1007/978-1-59745-361-5_3 DOI: https://doi.org/10.1007/978-1-59745-361-5_3
  36. Wagner J, Damaschke N, Yang B, Truong M, Guenther C, McCormick J, et al. Overexpression of the novel senescence marker β-galactosidase (GLB1) in prostate cancer predicts reduced PSA recurrence. PLoS One. 2015;10(4):e0124366. doi:.https://doi.org/10.1371/journal.pone.0124366 DOI: https://doi.org/10.1371/journal.pone.0124366
  37. Coppé JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010;5(1):99–118. doi:.https://doi.org/10.1146/annurev-pathol-121808-102144 DOI: https://doi.org/10.1146/annurev-pathol-121808-102144
  38. Rodier F, Campisi J. Four faces of cellular senescence. J Cell Biol. 2011;192(4):547–56. doi:.https://doi.org/10.1083/jcb.201009094 DOI: https://doi.org/10.1083/jcb.201009094
  39. Pérez-Mancera PA, Young AR, Narita M. Inside and out: the activities of senescence in cancer. Nat Rev Cancer. 2014;14(8):547–58. doi:.https://doi.org/10.1038/nrc3773 DOI: https://doi.org/10.1038/nrc3773
  40. Acosta JC, O’Loghlen A, Banito A, Guijarro MV, Augert A, Raguz S, et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell. 2008;133(6):1006–18. doi:.https://doi.org/10.1016/j.cell.2008.03.038 DOI: https://doi.org/10.1016/j.cell.2008.03.038
  41. Acosta JC, Gil J. A role for CXCR2 in senescence, but what about in cancer? Cancer Res. 2009;69(6):2167–70. doi:.https://doi.org/10.1158/0008-5472.CAN-08-3772 DOI: https://doi.org/10.1158/0008-5472.CAN-08-3772
  42. Kuilman T, Michaloglou C, Vredeveld LC, Douma S, van Doorn R, Desmet CJ, et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell. 2008;133(6):1019–31. doi:.https://doi.org/10.1016/j.cell.2008.03.039 DOI: https://doi.org/10.1016/j.cell.2008.03.039
  43. Di Mitri D, Alimonti A. Non-Cell-Autonomous Regulation of Cellular Senescence in Cancer. Trends Cell Biol. 2016;26(3):215–26. doi:.https://doi.org/10.1016/j.tcb.2015.10.005 DOI: https://doi.org/10.1016/j.tcb.2015.10.005
  44. Kang TW, Yevsa T, Woller N, Hoenicke L, Wuestefeld T, Dauch D, et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature. 2011;479(7374):547–51. doi:.https://doi.org/10.1038/nature10599 DOI: https://doi.org/10.1038/nature10599
  45. Lujambio A, Akkari L, Simon J, Grace D, Tschaharganeh DF, Bolden JE, et al. Non-cell-autonomous tumor suppression by p53. Cell. 2013;153(2):449–60. doi:.https://doi.org/10.1016/j.cell.2013.03.020 DOI: https://doi.org/10.1016/j.cell.2013.03.020
  46. Fridman WH, Pagès F, Sautès-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12(4):298–306. doi:.https://doi.org/10.1038/nrc3245 DOI: https://doi.org/10.1038/nrc3245
  47. Reimann M, Lee S, Loddenkemper C, Dörr JR, Tabor V, Aichele P, et al. Tumor stroma-derived TGF-beta limits myc-driven lymphomagenesis via Suv39h1-dependent senescence. Cancer Cell. 2010;17(3):262–72. doi:.https://doi.org/10.1016/j.ccr.2009.12.043 DOI: https://doi.org/10.1016/j.ccr.2009.12.043
  48. Coppé JP, Kauser K, Campisi J, Beauséjour CM. Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence. J Biol Chem. 2006;281(40):29568–74. doi:.https://doi.org/10.1074/jbc.M603307200 DOI: https://doi.org/10.1074/jbc.M603307200
  49. Rodier F, Coppé JP, Patil CK, Hoeijmakers WA, Muñoz DP, Raza SR, et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol. 2009;11(8):973–9. doi:.https://doi.org/10.1038/ncb1909 DOI: https://doi.org/10.1038/ncb1909
  50. Hubackova S, Krejcikova K, Bartek J, Hodny Z. IL1- and TGFβ-Nox4 signaling, oxidative stress and DNA damage response are shared features of replicative, oncogene-induced, and drug-induced paracrine ‘bystander senescence’. Aging (Albany NY). 2012;4(12):932–51. doi:.https://doi.org/10.18632/aging.100520 DOI: https://doi.org/10.18632/aging.100520
  51. Krtolica A, Parrinello S, Lockett S, Desprez PY, Campisi J. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci USA. 2001;98(21):12072–7. doi:.https://doi.org/10.1073/pnas.211053698 DOI: https://doi.org/10.1073/pnas.211053698
  52. Liu D, Hornsby PJ. Senescent human fibroblasts increase the early growth of xenograft tumors via matrix metalloproteinase secretion. Cancer Res. 2007;67(7):3117–26. doi:.https://doi.org/10.1158/0008-5472.CAN-06-3452 DOI: https://doi.org/10.1158/0008-5472.CAN-06-3452
  53. Jackson JG, Pant V, Li Q, Chang LL, Quintás-Cardama A, Garza D, et al. p53-mediated senescence impairs the apoptotic response to chemotherapy and clinical outcome in breast cancer. Cancer Cell. 2012;21(6):793–806. doi:.https://doi.org/10.1016/j.ccr.2012.04.027 DOI: https://doi.org/10.1016/j.ccr.2012.04.027
  54. Guerra C, Collado M, Navas C, Schuhmacher AJ, Hernández-Porras I, Cañamero M, et al. Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence. Cancer Cell. 2011;19(6):728–39. doi:.https://doi.org/10.1016/j.ccr.2011.05.011 DOI: https://doi.org/10.1016/j.ccr.2011.05.011
  55. Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature. 2013;499(7456):97–101. doi:.https://doi.org/10.1038/nature12347 DOI: https://doi.org/10.1038/nature12347
  56. Toso A, Di Mitri D, Alimonti A. Enhancing chemotherapy efficacy by reprogramming the senescence-associated secretory phenotype of prostate tumors: A way to reactivate the antitumor immunity. OncoImmunology. 2015;4(3):e994380. doi:.https://doi.org/10.4161/2162402X.2014.994380 DOI: https://doi.org/10.4161/2162402X.2014.994380
  57. Herranz N, Gallage S, Mellone M, Wuestefeld T, Klotz S, Hanley CJ, et al. mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nat Cell Biol. 2015;17(9):1205–17. doi:.https://doi.org/10.1038/ncb3225 DOI: https://doi.org/10.1038/ncb3225
  58. Laberge RM, Sun Y, Orjalo AV, Patil CK, Freund A, Zhou L, et al. MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat Cell Biol. 2015;17(8):1049–61. doi:.https://doi.org/10.1038/ncb3195 DOI: https://doi.org/10.1038/ncb3195
  59. Tasdemir N, Banito A, Roe JS, Alonso-Curbelo D, Camiolo M, Tschaharganeh DF, et al. BRD4 Connects Enhancer Remodeling to Senescence Immune Surveillance. Cancer Discov. 2016;6(6):612–29. doi:.https://doi.org/10.1158/2159-8290.CD-16-0217 DOI: https://doi.org/10.1158/2159-8290.CD-16-0217
  60. Liu S, Uppal H, Demaria M, Desprez PY, Campisi J, Kapahi P. Simvastatin suppresses breast cancer cell proliferation induced by senescent cells. Sci Rep. 2015;5:17895. doi:.https://doi.org/10.1038/srep17895 DOI: https://doi.org/10.1038/srep17895
  61. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol. 2012;12(4):253–68. doi:.https://doi.org/10.1038/nri3175 DOI: https://doi.org/10.1038/nri3175
  62. Di Mitri D, Toso A, Alimonti A. Molecular Pathways: Targeting Tumor-Infiltrating Myeloid-Derived Suppressor Cells for Cancer Therapy. Clin Cancer Res. 2015;21(14):3108–12. doi:.https://doi.org/10.1158/1078-0432.CCR-14-2261 DOI: https://doi.org/10.1158/1078-0432.CCR-14-2261
  63. Wesolowski R, Markowitz J, Carson WE, 3rd. Myeloid derived suppressor cells - a new therapeutic target in the treatment of cancer. J Immunother Cancer. 2013;1(1):10. doi:.https://doi.org/10.1186/2051-1426-1-10 DOI: https://doi.org/10.1186/2051-1426-1-10
  64. Vuk-Pavlović S, Bulur PA, Lin Y, Qin R, Szumlanski CL, Zhao X, et al. Immunosuppressive CD14+HLA-DRlow/- monocytes in prostate cancer. Prostate. 2010;70(4):443–55. doi:.https://doi.org/10.1002/pros.21078 DOI: https://doi.org/10.1002/pros.21078
  65. Bronte V, Kasic T, Gri G, Gallana K, Borsellino G, Marigo I, et al. Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers. J Exp Med. 2005;201(8):1257–68. doi:.https://doi.org/10.1084/jem.20042028 DOI: https://doi.org/10.1084/jem.20042028
  66. Diaz-Montero CM, Salem ML, Nishimura MI, Garrett-Mayer E, Cole DJ, Montero AJ. Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother. 2009;58(1):49–59. doi:.https://doi.org/10.1007/s00262-008-0523-4 DOI: https://doi.org/10.1007/s00262-008-0523-4
  67. Yang L, DeBusk LM, Fukuda K, Fingleton B, Green-Jarvis B, Shyr Y, et al. Expansion of myeloid immune suppressor Gr+CD11b+ cells in tumor-bearing host directly promotes tumor angiogenesis. Cancer Cell. 2004;6(4):409–21. doi:.https://doi.org/10.1016/j.ccr.2004.08.031 DOI: https://doi.org/10.1016/j.ccr.2004.08.031
  68. Murdoch C, Muthana M, Coffelt SB, Lewis CE. The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer. 2008;8(8):618–31. doi:.https://doi.org/10.1038/nrc2444 DOI: https://doi.org/10.1038/nrc2444
  69. Shojaei F, Wu X, Zhong C, Yu L, Liang XH, Yao J, et al. Bv8 regulates myeloid-cell-dependent tumour angiogenesis. Nature. 2007;450(7171):825–31. doi:.https://doi.org/10.1038/nature06348 DOI: https://doi.org/10.1038/nature06348
  70. Kodumudi KN, Woan K, Gilvary DL, Sahakian E, Wei S, Djeu JY. A novel chemoimmunomodulating property of docetaxel: suppression of myeloid-derived suppressor cells in tumor bearers. Clin Cancer Res. 2010;16(18):4583–94. doi:.https://doi.org/10.1158/1078-0432.CCR-10-0733 DOI: https://doi.org/10.1158/1078-0432.CCR-10-0733
  71. Sumida K, Wakita D, Narita Y, Masuko K, Terada S, Watanabe K, et al. Anti-IL-6 receptor mAb eliminates myeloid-derived suppressor cells and inhibits tumor growth by enhancing T-cell responses. Eur J Immunol. 2012;42(8):2060–72. doi:.https://doi.org/10.1002/eji.201142335 DOI: https://doi.org/10.1002/eji.201142335
  72. Crittenden MR, Savage T, Cottam B, Bahjat KS, Redmond WL, Bambina S, et al. The peripheral myeloid expansion driven by murine cancer progression is reversed by radiation therapy of the tumor. PLoS One. 2013;8(7):e69527. doi:.https://doi.org/10.1371/journal.pone.0069527 DOI: https://doi.org/10.1371/journal.pone.0069527
  73. Vilgelm AE, Johnson DB, Richmond A. Combinatorial approach to cancer immunotherapy: strength in numbers. J Leukoc Biol. 2016;100(2):275–90. doi:.https://doi.org/10.1189/jlb.5RI0116-013RR DOI: https://doi.org/10.1189/jlb.5RI0116-013RR
  74. Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell. 2015;161(2):205–14. doi:.https://doi.org/10.1016/j.cell.2015.03.030 DOI: https://doi.org/10.1016/j.cell.2015.03.030
  75. Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N, et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015;14(4):644–58. doi:.https://doi.org/10.1111/acel.12344 DOI: https://doi.org/10.1111/acel.12344
  76. Zhu Y, Tchkonia T, Fuhrmann-Stroissnigg H, Dai HM, Ling YY, Stout MB, et al. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell. 2016;15(3):428–35. doi:.https://doi.org/10.1111/acel.12445 DOI: https://doi.org/10.1111/acel.12445
  77. Dörr JR, Yu Y, Milanovic M, Beuster G, Zasada C, Däbritz JH, et al. Synthetic lethal metabolic targeting of cellular senescence in cancer therapy. Nature. 2013;501(7467):421–5. doi:.https://doi.org/10.1038/nature12437 DOI: https://doi.org/10.1038/nature12437

Most read articles by the same author(s)