Review Article | Published:

Cell death in cancer in the era of precision medicine

Genes & Immunity (2018) | Download Citation


Tumors constitute a large class of diseases that affect different organs and cell lineages. The molecular characterization of cancers of a given type has revealed an extraordinary heterogeneity in terms of genetic alterations and DNA mutations; heterogeneity that is further highlighted by single-cell DNA sequencing of individual patients. To address these issues, drugs that specifically target genes or altered pathways in cancer cells are continuously developed. Indeed, the genetic fingerprint of individual tumors can direct the modern therapeutic approaches to selectively hit the tumor cells while sparing the healthy ones. In this context, the concept of precision medicine finds a vast field of application. In this review, we will briefly list some classes of target drugs (Bcl-2 family modulators, Tyrosine Kinase modulators, PARP inhibitors, and growth factors inhibitors) and discuss the application of immunotherapy in tumors (T cell-mediated immunotherapy and CAR-T cells) that in recent years has drastically changed the prognostic outlook of aggressive cancers. We will also consider how apoptosis could represent a primary end point in modern cancer therapy and how “classic” chemotherapeutic drugs that induce apoptosis are still utilized in therapeutic schedules that involve the use of target drugs or immunotherapy to optimize the antitumor response.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

    Burrell RA, McGranahan N, Bartek J, Swanton C. The causes and consequences of genetic heterogeneity in cancer evolution. Nature. 2013;501:338–45.

  2. 2.

    Hiley CT, Le Quesne J, Santis G, Sharpe R, de Castro DG, Middleton G, et al. Challenges in molecular testing in non-small-cell lung cancer patients with advanced disease. Lancet. 2016;388:1002–11.

  3. 3.

    McGranahan N, Swanton C. Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. Cancer Cell. 2015;27:15–26.

  4. 4.

    Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science. 2015;348:62–8.

  5. 5.

    Sahin U, Tureci O. Personalized vaccines for cancer immunotherapy. Science. 2018;359:1355–60.

  6. 6.

    Birkeland E, Zhang S, Poduval D, Geisler J, Nakken S, Vodak D, et al. Patterns of genomic evolution in advanced melanoma. Nat Commun. 2018;9:2665.

  7. 7.

    Schmitz R, Wright GW, Huang DW, Johnson CA, Phelan JD, Wang JQ, et al. Genetics and pathogenesis of diffuse large B-cell lymphoma. N Engl J Med. 2018;378:1396–407.

  8. 8.

    Kim C, Gao R, Sei E, Brandt R, Hartman J, Hatschek T, et al. Chemoresistance evolution in triple-negative breast cancer delineated by single-cell sequencing. Cell. 2018;173:879–893 e13.

  9. 9.

    Jacob J, Durand T, Feuvret L, Mazeron JJ, Delattre JY, Hoang-Xuan K. et al. Cognitive impairment and morphological changes after radiation therapy in brain tumors: a review. Radiother Oncol. 2018;28:221–228.

  10. 10.

    Levis BE, Binkley PF, Shapiro CL. Cardiotoxic effects of anthracycline-based therapy: what is the evidence and what are the potential harms? Lancet Oncol. 2017;18:e445–e456.

  11. 11.

    Aguirre AJ, Nowak JA, Camarda ND, Moffitt RA, Ghazani AA, Hazar-Rethinam M. et al. Real-time genomic characterization of advanced pancreatic cancer to enable precision medicine. Cancer Discov. 2018;8:1096–1111.

  12. 12.

    Xu C, Nikolova O, Basom RS, Mitchell RM, Shaw R, Moser RD, et al. Functional Precision Medicine Identifies Novel Druggable Targets and Therapeutic Options in Head and Neck Cancer. Clin Cancer Res. 2018;24:2828–43.

  13. 13.

    Wang J, Yao Z, Jonsson P, Allen AN, Qin ACR, Uddin S. et al. A secondary mutation in BRAF confers resistance to RAF inhibition in a BRAF V600E-mutant brain tumor. Cancer Discov. 2018;8:1130–1141.

  14. 14.

    Juratli TA, Stasik S, Zolal A, Schuster C, Richter S, Daubner D et al. TERT promoter mutation detection in cell-free tumor-derived DNA in patients with IDH wild-type glioblastomas - a pilot prospective study. Clin Cancer Res 2018.

  15. 15.

    Kjaergaard J, Hatfield S, Jones G, Ohta A, Sitkovsky M. A2A adenosine receptor gene deletion or synthetic A2A antagonist liberate tumor-reactive CD8(+) T Cells from tumor-induced immunosuppression. J Immunol. 2018;201:782–91.

  16. 16.

    Tanaka T, Nakajima-Takagi Y, Aoyama K, Tara S, Oshima M, Saraya A, et al. Internal deletion of BCOR reveals a tumor suppressor function for BCOR in T lymphocyte malignancies. J Exp Med. 2017;214:2901–13.

  17. 17.

    Brasacchio D, Alsop AE, Noori T, Lufti M, Iyer S, Simpson KJ, et al. Epigenetic control of mitochondrial cell death through PACS1-mediated regulation of BAX/BAK oligomerization. Cell Death Differ. 2017;24:961–70.

  18. 18.

    Yuan K, Lei Y, Chen HN, Chen Y, Zhang T, Li K, et al. HBV-induced ROS accumulation promotes hepatocarcinogenesis through Snail-mediated epigenetic silencing of SOCS3. Cell Death Differ. 2016;23:616–27.

  19. 19.

    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.

  20. 20.

    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

  21. 21.

    Bell RAV, Megeney LA. Evolution of caspase-mediated cell death and differentiation: twins separated at birth. Cell Death Differ. 2017;24:1359–68.

  22. 22.

    Pihan P, Carreras-Sureda A, Hetz C. BCL-2 family: integrating stress responses at the ER to control cell demise. Cell Death Differ. 2017;24:1478–87.

  23. 23.

    Van Aken O, Pogson BJ. Convergence of mitochondrial and chloroplastic ANAC017/PAP-dependent retrograde signalling pathways and suppression of programmed cell death. Cell Death Differ. 2017;24:955–60.

  24. 24.

    Llambi F, Moldoveanu T, Tait SW, Bouchier-Hayes L, Temirov J, McCormick LL, et al. A unified model of mammalian BCL-2 protein family interactions at the mitochondria. Mol Cell. 2011;44:517–31.

  25. 25.

    Opferman JT. Attacking cancer’s Achilles heel: antagonism of anti-apoptotic BCL-2 family members. FEBS J. 2016;283:2661–75.

  26. 26.

    Glab JA, Doerflinger M, Nedeva C, Jose I, Mbogo GW, Paton JC, et al. DR5 and caspase-8 are dispensable in ER stress-induced apoptosis. Cell Death Differ. 2017;24:944–50.

  27. 27.

    Anstee NS, Vandenberg CJ, Campbell KJ, Hughes PD, O’Reilly LA, Cory S. Overexpression of Mcl-1 exacerbates lymphocyte accumulation and autoimmune kidney disease in lpr mice. Cell Death Differ. 2017;24:397–408.

  28. 28.

    Carrington EM, Zhan Y, Brady JL, Zhang JG, Sutherland RM, Anstee NS, et al. Anti-apoptotic proteins BCL-2, MCL-1 and A1 summate collectively to maintain survival of immune cell populations both in vitro and in vivo. Cell Death Differ. 2017;24:878–88.

  29. 29.

    Cory S, Vaux DL, Strasser A, Harris AW, Adams JM. Insights from Bcl-2 and Myc: malignancy involves abrogation of apoptosis as well as sustained proliferation. Cancer Res. 1999;59(7 Suppl):1685s–1692s.

  30. 30.

    Linette GP, Hess JL, Sentman CL, Korsmeyer SJ. Peripheral T-cell lymphoma in lckpr-bcl-2 transgenic mice. Blood. 1995;86:1255–60.

  31. 31.

    Schwickart M, Huang X, Lill JR, Liu J, Ferrando R, French DM, et al. Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival. Nature. 2010;463:103–7.

  32. 32.

    Karpel-Massler G, Ishida CT, Zhang Y, Halatsch ME, Westhoff MA, Siegelin MD. Targeting intrinsic apoptosis and other forms of cell death by BH3-mimetics in glioblastoma. Expert Opin Drug Discov. 2017;12:1031–40.

  33. 33.

    Peperzak V, Slinger E, Ter Burg J, Eldering E. Functional disparities among BCL-2 members in tonsillar and leukemic B-cell subsets assessed by BH3-mimetic profiling. Cell Death Differ. 2017;24:111–9.

  34. 34.

    Rohrbeck L, Gong JN, Lee EF, Kueh AJ, Behren A, Tai L, et al. Hepatocyte growth factor renders BRAF mutant human melanoma cell lines resistant to PLX4032 by downregulating the pro-apoptotic BH3-only proteins PUMA and BIM. Cell Death Differ. 2016;23:2054–62.

  35. 35.

    Oliver CL, Bauer JA, Wolter KG, Ubell ML, Narayan A, O’Connell KM, et al. In vitro effects of the BH3 mimetic, (-)-gossypol, on head and neck squamous cell carcinoma cells. Clin Cancer Res. 2004;10:7757–63.

  36. 36.

    Park HA, Licznerski P, Mnatsakanyan N, Niu Y, Sacchetti S, Wu J, et al. Inhibition of Bcl-xL prevents pro-death actions of DeltaN-Bcl-xL at the mitochondrial inner membrane during glutamate excitotoxicity. Cell Death Differ. 2017;24:1963–74.

  37. 37.

    Czabotar PE, Westphal D, Dewson G, Ma S, Hockings C, Fairlie WD, et al. Bax crystal structures reveal how BH3 domains activate Bax and nucleate its oligomerization to induce apoptosis. Cell. 2013;152:519–31.

  38. 38.

    Xin M, Li R, Xie M, Park D, Owonikoko TK, Sica GL, et al. Small-molecule Bax agonists for cancer therapy. Nat Commun. 2014;5:4935.

  39. 39.

    Montero J, Letai A. Why do BCL-2 inhibitors work and where should we use them in the clinic? Cell Death Differ. 2018;25:56–64.

  40. 40.

    Adams JM, Cory S. The BCL-2 arbiters of apoptosis and their growing role as cancer targets. Cell Death Differ. 2018;25:27–36.

  41. 41.

    Reed JC. Bcl-2 on the brink of breakthroughs in cancer treatment. Cell Death Differ. 2018;25:3–6.

  42. 42.

    Mayers JR. Metabolic markers as cancer clues. Science. 2017;358:1265.

  43. 43.

    Palazzo E, Kellett MD, Cataisson C, Bible PW, Bhattacharya S, Sun HW, et al. A novel DLX3-PKC integrated signaling network drives keratinocyte differentiation. Cell Death Differ. 2017;24:717–30.

  44. 44.

    Pieraccioli M, Nicolai S, Pitolli C, Agostini M, Antonov A, Malewicz M, et al. ZNF281 inhibits neuronal differentiation and is a prognostic marker for neuroblastoma. Proc Natl Acad Sci USA. 2018;115:7356–61.

  45. 45.

    Almohazey D, Lo YH, Vossler CV, Simmons AJ, Hsieh JJ, Bucar EB, et al. The ErbB3 receptor tyrosine kinase negatively regulates Paneth cells by PI3K-dependent suppression of Atoh1. Cell Death Differ. 2017;24:855–65.

  46. 46.

    Gnani D, Romito I, Artuso S, Chierici M, De Stefanis C, Panera N, et al. Focal adhesion kinase depletion reduces human hepatocellular carcinoma growth by repressing enhancer of zeste homolog 2. Cell Death Differ. 2017;24:889–902.

  47. 47.

    Hyman DM, Piha-Paul SA, Won H, Rodon J, Saura C, Shapiro GI, et al. HER kinase inhibition in patients with HER2- and HER3-mutant cancers. Nature. 2018;554:189–94.

  48. 48.

    Tam CS, Anderson MA, Pott C, Agarwal R, Handunnetti S, Hicks RJ, et al. Ibrutinib plus Venetoclax for the Treatment of Mantle-Cell Lymphoma. N Engl J Med. 2018;378:1211–23.

  49. 49.

    Carroll M, Ohno-Jones S, Tamura S, Buchdunger E, Zimmermann J, Lydon NB, et al. CGP 57148, a tyrosine kinase inhibitor, inhibits the growth of cells expressing BCR-ABL, TEL-ABL, and TEL-PDGFR fusion proteins. Blood. 1997;90:4947–52.

  50. 50.

    Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996;2:561–6.

  51. 51.

    O’Hare T, Walters DK, Deininger MW, Druker BJ. AMN107: tightening the grip of imatinib. Cancer Cell. 2005;7:117–9.

  52. 52.

    Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science. 2004;305:399–401.

  53. 53.

    Maris JM. Recent advances in neuroblastoma. N Engl J Med. 2010;362:2202–11.

  54. 54.

    Vitali R, Mancini C, Cesi V, Tanno B, Piscitelli M, Mancuso M, et al. Activity of tyrosine kinase inhibitor Dasatinib in neuroblastoma cells in vitro and in orthotopic mouse model. Int J Cancer. 2009;125:2547–55.

  55. 55.

    Arai S, Jonas O, Whitman M, Corey E, Balk SP, Chen S. Tyrosine kinase inhibitors increase MCL1 degradation and in combination with BCLXL/BCL2 inhibitors drive prostate cancer apoptosis. Clin Cancer Res 2018.

  56. 56.

    Reiff SD, Muhowski EM, Guinn D, Lehman A, Fabian CA, Cheney C. et al. Non-covalent inhibition of C481S Bruton’s tyrosine kinase by GDC-0853: a new treatment strategy for ibrutinib resistant CLL. Blood. 2018;132:1039–1049.

  57. 57.

    Zhai W, Sun Y, Guo C, Hu G, Wang M, Zheng J, et al. LncRNA-SARCC suppresses renal cell carcinoma (RCC) progression via altering the androgen receptor(AR)/miRNA-143-3p signals. Cell Death Differ. 2017;24:1502–17.

  58. 58.

    Bassi C, Li YT, Khu K, Mateo F, Baniasadi PS, Elia A, et al. The acetyltransferase Tip60 contributes to mammary tumorigenesis by modulating DNA repair. Cell Death Differ. 2016;23:1198–208.

  59. 59.

    Chapuy B, Stewart C, Dunford AJ, Kim J, Kamburov A, Redd RA, et al. Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. Nat Med. 2018;24:679–90.

  60. 60.

    Chernova T, Sun XM, Powley IR, Galavotti S, Grosso S, Murphy FA, et al. Molecular profiling reveals primary mesothelioma cell lines recapitulate human disease. Cell Death Differ. 2016;23:1152–64.

  61. 61.

    Menghi F, Barthel FP, Yadav V, Tang M, Ji B, Tang Z. et al. The Tandem duplicator phenotype is a prevalent genome-wide cancer configuration driven by distinct gene mutations. Cancer Cell. 2018;34:197–210.e5.

  62. 62.

    Aggarwal M, Saxena R, Sinclair E, Fu Y, Jacobs A, Dyba M, et al. Reactivation of mutant p53 by a dietary-related compound phenethyl isothiocyanate inhibits tumor growth. Cell Death Differ. 2016;23:1615–27.

  63. 63.

    Cammareri P, Vincent DF, Hodder MC, Ridgway RA, Murgia C, Nobis M, et al. TGFbeta pathway limits dedifferentiation following WNT and MAPK pathway activation to suppress intestinal tumourigenesis. Cell Death Differ. 2017;24:1681–93.

  64. 64.

    Eritja N, Felip I, Dosil MA, Vigezzi L, Mirantes C, Yeramian A, et al. A Smad3-PTEN regulatory loop controls proliferation and apoptotic responses to TGF-beta in mouse endometrium. Cell Death Differ. 2017;24:1443–58.

  65. 65.

    Ng KP, Hillmer AM, Chuah CT, Juan WC, Ko TK, Teo AS, et al. A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer. Nat Med. 2012;18:521–8.

  66. 66.

    Lord CJ, Ashworth A. The DNA damage response and cancer therapy. Nature. 2012;481:287–94.

  67. 67.

    Hoeijmakers JH. DNA damage, aging, and cancer. N Engl J Med. 2009;361:1475–85.

  68. 68.

    Gupta R, Somyajit K, Narita T, Maskey E, Stanlie A, Kremer M, et al. DNA repair network analysis reveals shieldin as a key regulator of NHEJ and PARP inhibitor sensitivity. Cell. 2018;173:972–988 e23.

  69. 69.

    Nicolai S, Rossi A, Di Daniele N, Melino G, Annicchiarico-Petruzzelli M, Raschella G. DNA repair and aging: the impact of the p53 family. Aging. 2015;7:1050–65.

  70. 70.

    Malewicz M, Perlmann T. Function of transcription factors at DNA lesions in DNA repair. Exp Cell Res. 2014;329:94–100.

  71. 71.

    Pieraccioli M, Nicolai S, Antonov A, Somers J, Malewicz M, Melino G, et al. ZNF281 contributes to the DNA damage response by controlling the expression of XRCC2 and XRCC4. Oncogene. 2016;35:2592–601.

  72. 72.

    Raschella G, Melino G, Malewicz M. New factors in mammalian DNA repair-the chromatin connection. Oncogene. 2017;36:4673–81.

  73. 73.

    Hawley BR, Lu WT, Wilczynska A, Bushell M. The emerging role of RNAs in DNA damage repair. Cell Death Differ. 2017;24:580–7.

  74. 74.

    Grigaravicius P, Kaminska E, Hubner CA, McKinnon PJ, von Deimling A, Frappart PO. Rint1 inactivation triggers genomic instability, ER stress and autophagy inhibition in the brain. Cell Death Differ. 2016;23:454–68.

  75. 75.

    Rustighi A, Zannini A, Campaner E, Ciani Y, Piazza S, Del Sal G. PIN1 in breast development and cancer: a clinical perspective. Cell Death Differ. 2017;24:200–11.

  76. 76.

    Baran K, Yang M, Dillon CP, Samson LL, Green DR. The proline rich domain of p53 is dispensable for MGMT-dependent DNA repair and cell survival following alkylation damage. Cell Death Differ. 2017;24:1925–36.

  77. 77.

    Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature. 2009;461:1071–8.

  78. 78.

    Rodriguez-Vargas JM, Rodriguez MI, Majuelos-Melguizo J, Garcia-Diaz A, Gonzalez-Flores A, Lopez-Rivas A, et al. Autophagy requires poly(adp-ribosyl)ation-dependent AMPK nuclear export. Cell Death Differ. 2016;23:2007–18.

  79. 79.

    Purnell MR, Whish WJ. Novel inhibitors of poly(ADP-ribose) synthetase. Biochem J. 1980;185:775–7.

  80. 80.

    Terada M, Fujiki H, Marks PA, Sugimura T. Induction of erythroid differentiation of murine erythroleukemia cells by nicotinamide and related compounds. Proc Natl Acad Sci USA. 1979;76:6411–4.

  81. 81.

    Delgado-Camprubi M, Esteras N, Soutar MP, Plun-Favreau H, Abramov AY. Deficiency of Parkinson’s disease-related gene Fbxo7 is associated with impaired mitochondrial metabolism by PARP activation. Cell Death Differ. 2017;24:120–31.

  82. 82.

    You MH, Kim BM, Chen CH, Begley MJ, Cantley LC, Lee TH. Death-associated protein kinase 1 phosphorylates NDRG2 and induces neuronal cell death. Cell Death Differ. 2017;24:238–50.

  83. 83.

    Lord CJ, Ashworth A. PARP inhibitors: synthetic lethality in the clinic. Science. 2017;355:1152–8.

  84. 84.

    Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373:1697–708.

  85. 85.

    Pujade-Lauraine E, Ledermann JA, Selle F, Gebski V, Penson RT, Oza AM, et al. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18:1274–84.

  86. 86.

    de Bono J, Ramanathan RK, Mina L, Chugh R, Glaspy J, Rafii S, et al. Phase I, dose-escalation, two-part trial of the PARP inhibitor talazoparib in patients with advanced germline BRCA1/2 mutations and selected sporadic cancers. Cancer Discov. 2017;7:620–9.

  87. 87.

    Bluemn EG, Coleman IM, Lucas JM, Coleman RT, Hernandez-Lopez S, Tharakan R, et al. Androgen receptor pathway-independent prostate cancer is sustained through FGF signaling. Cancer Cell. 2017;32:474–489 e6.

  88. 88.

    Clement F, Xu X, Donini CF, Clement A, Omarjee S, Delay E, et al. Long-term exposure to bisphenol A or benzo(a)pyrene alters the fate of human mammary epithelial stem cells in response to BMP2 and BMP4, by pre-activating BMP signaling. Cell Death Differ. 2017;24:155–66.

  89. 89.

    Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182–6.

  90. 90.

    Kerbel RS. Tumor angiogenesis. N Engl J Med. 2008;358:2039–49.

  91. 91.

    Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature. 2005;438:967–74.

  92. 92.

    Jayson GC, Kerbel R, Ellis LM, Harris AL. Antiangiogenic therapy in oncology: current status and future directions. Lancet. 2016;388:518–29.

  93. 93.

    Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P, et al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science. 1998;279:563–6.

  94. 94.

    LeRoith D, Helman L. The new kid on the block(ade) of the IGF-1 receptor. Cancer Cell. 2004;5:201–2.

  95. 95.

    Garcia-Echeverria C, Pearson MA, Marti A, Meyer T, Mestan J, Zimmermann J, et al. In vivo antitumor activity of NVP-AEW541-A novel, potent, and selective inhibitor of the IGF-IR kinase. Cancer Cell. 2004;5:231–9.

  96. 96.

    Tanno B, Mancini C, Vitali R, Mancuso M, McDowell HP, Dominici C, et al. Down-regulation of insulin-like growth factor I receptor activity by NVP-AEW541 has an antitumor effect on neuroblastoma cells in vitro and in vivo. Clin Cancer Res. 2006;12:6772–80.

  97. 97.

    Agostini M, Romeo F, Inoue S, Niklison-Chirou MV, Elia AJ, Dinsdale D, et al. Metabolic reprogramming during neuronal differentiation. Cell Death Differ. 2016;23:1502–14.

  98. 98.

    Amelio I, Cutruzzola F, Antonov A, Agostini M, Melino G. Serine and glycine metabolism in cancer. Trends Biochem Sci. 2014;39:191–8.

  99. 99.

    Amelio I, Melino G, Frezza C. Exploiting tumour addiction with a serine and glycine-free diet. Cell Death Differ. 2017;24:1311–3.

  100. 100.

    Sciacovelli M, Frezza C. Fumarate drives EMT in renal cancer. Cell Death Differ. 2017;24:1–2.

  101. 101.

    Sciacovelli M, Goncalves E, Johnson TI, Zecchini VR, da Costa AS, Gaude E, et al. Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Nature. 2016;537:544–7.

  102. 102.

    Zaugg K, Yao Y, Reilly PT, Kannan K, Kiarash R, Mason J, et al. Carnitine palmitoyltransferase 1C promotes cell survival and tumor growth under conditions of metabolic stress. Genes Dev. 2011;25:1041–51.

  103. 103.

    Maddocks ODK, Athineos D, Cheung EC, Lee P, Zhang T, van den Broek NJF, et al. Modulating the therapeutic response of tumours to dietary serine and glycine starvation. Nature. 2017;544:372–6.

  104. 104.

    Bourdon JC, Laurenzi VD, Melino G, Lane D. p53: 25 years of research and more questions to answer. Cell Death Differ. 2003;10:397–9.

  105. 105.

    Rufini A, Niklison-Chirou MV, Inoue S, Tomasini R, Harris IS, Marino A, et al. TAp73 depletion accelerates aging through metabolic dysregulation. Genes Dev. 2012;26:2009–14.

  106. 106.

    Seitz SJ, Schleithoff ES, Koch A, Schuster A, Teufel A, Staib F, et al. Chemotherapy-induced apoptosis in hepatocellular carcinoma involves the p53 family and is mediated via the extrinsic and the intrinsic pathway. Int J Cancer. 2010;126:2049–66.

  107. 107.

    Niklison-Chirou MV, Erngren I, Engskog M, Haglof J, Picard D, Remke M, et al. TAp73 is a marker of glutamine addiction in medulloblastoma. Genes Dev. 2017;31:1738–53.

  108. 108.

    Marini A, Rotblat B, Sbarrato T, Niklison-Chirou MV, Knight JRP, Dudek K, et al. TAp73 contributes to the oxidative stress response by regulating protein synthesis. Proc Natl Acad Sci USA. 2018;115:6219–24.

  109. 109.

    Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420:860–7.

  110. 110.

    Field J, Fox A, Jordan MA, Baxter AG, Spelman T, Gresle M, et al. Interleukin-2 receptor-alpha proximal promoter hypomethylation is associated with multiple sclerosis. Genes Immun. 2017;18:59–66.

  111. 111.

    Karin M, Clevers H. Reparative inflammation takes charge of tissue regeneration. Nature. 2016;529:307–15.

  112. 112.

    Ng GZ, Sutton P. The MUC1 mucin specifically inhibits activation of the NLRP3 inflammasome. Genes Immun. 2016;17:203–6.

  113. 113.

    Smith LM, Weissenburger-Moser LA, Heires AJ, Bailey KL, Romberger DJ, LeVan TD. Epistatic effect of TLR-1, -6 and -10 polymorphisms on organic dust-mediated cytokine response. Genes Immun. 2017;18:67–74.

  114. 114.

    Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature. 2017;541:321–30.

  115. 115.

    Garg AD, Romano E, Rufo N, Agostinis P. Immunogenic versus tolerogenic phagocytosis during anticancer therapy: mechanisms and clinical translation. Cell Death Differ. 2016;23:938–51.

  116. 116.

    June CH, Sadelain M. Chimeric Antigen Receptor Therapy. N Engl J Med. 2018;379:64–73.

  117. 117.

    Yamazaki T, Pitt JM, Vetizou M, Marabelle A, Flores C, Rekdal O, et al. The oncolytic peptide LTX-315 overcomes resistance of cancers to immunotherapy with CTLA4 checkpoint blockade. Cell Death Differ. 2016;23:1004–15.

  118. 118.

    de Jong VM, van der Slik AR, Laban S, van ‘t Slot R, Koeleman BP, Zaldumbide A, et al. Survival of autoreactive T lymphocytes by microRNA-mediated regulation of apoptosis through TRAIL and Fas in type 1 diabetes. Genes Immun. 2016;17:342–8.

  119. 119.

    Hussman JP, Beecham AH, Schmidt M, Martin ER, McCauley JL, Vance JM, et al. GWAS analysis implicates NF-kappaB-mediated induction of inflammatory T cells in multiple sclerosis. Genes Immun. 2016;17:305–12.

  120. 120.

    Ise W, Kohyama M, Nutsch KM, Lee HM, Suri A, Unanue ER, et al. CTLA-4 suppresses the pathogenicity of self antigen-specific T cells by cell-intrinsic and cell-extrinsic mechanisms. Nat Immunol. 2010;11:129–35.

  121. 121.

    Lu X, Horner JW, Paul E, Shang X, Troncoso P, Deng P, et al. Effective combinatorial immunotherapy for castration-resistant prostate cancer. Nature. 2017;543:728–32.

  122. 122.

    Eyquem J, Mansilla-Soto J, Giavridis T, van der Stegen SJ, Hamieh M, Cunanan KM, et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature. 2017;543:113–7.

  123. 123.

    Jena B, Dotti G, Cooper LJ. Redirecting T-cell specificity by introducing a tumor-specific chimeric antigen receptor. Blood. 2010;116:1035–44.

  124. 124.

    Kim MY, Yu KR, Kenderian SS, Ruella M, Chen S, Shin TH, et al. Genetic inactivation of CD33 in hematopoietic stem cells to enable CAR T cell immunotherapy for acute myeloid leukemia. Cell. 2018;173:1439–53 e19.

  125. 125.

    Numbenjapon T, Serrano LM, Chang WC, Forman SJ, Jensen MC, Cooper LJ. Antigen-independent and antigen-dependent methods to numerically expand CD19-specific CD8+T cells. Exp Hematol. 2007;35:1083–90.

  126. 126.

    Lingel H, Wissing J, Arra A, Schanze D, Lienenklaus S, Klawonn F, et al. CTLA-4-mediated posttranslational modifications direct cytotoxic T-lymphocyte differentiation. Cell Death Differ. 2017;24:1739–49.

  127. 127.

    Forde PM, Chaft JE, Smith KN, Anagnostou V, Cottrell TR, Hellmann MD, et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med. 2018;378:1976–86.

  128. 128.

    Kearney CJ, Lalaoui N, Freeman AJ, Ramsbottom KM, Silke J, Oliaro J. PD-L1 and IAPs co-operate to protect tumors from cytotoxic lymphocyte-derived TNF. Cell Death Differ. 2017;24:1705–16.

  129. 129.

    Shen J, Ju Z, Zhao W, Wang L, Peng Y, Ge Z. et al. ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Nat Med. 2018;24:556–62.

  130. 130.

    Gibney GT, Weiner LM, Atkins MB. Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol. 2016;17:e542–e551.

  131. 131.

    Hedrick SM, Cohen DI, Nielsen EA, Davis MM. Isolation of cDNA clones encoding T cell-specific membrane-associated proteins. Nature. 1984;308:149–53.

  132. 132.

    Yanagi Y, Yoshikai Y, Leggett K, Clark SP, Aleksander I, Mak TW. A human T cell-specific cDNA clone encodes a protein having extensive homology to immunoglobulin chains. Nature. 1984;308:145–9.

  133. 133.

    Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science. 1995;270:985–8.

  134. 134.

    Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271:1734–6.

  135. 135.

    Franckaert D, Collin R, Dooley J, Wallis RH, Poussier P, Liston A, et al. An orthologous non-MHC locus in rats and mice is linked to CD4(+) and CD8(+) T-cell proportion. Genes Immun. 2017;18:118–26.

  136. 136.

    Glodde N, Bald T, van den Boorn-Konijnenberg D, Nakamura K, O’Donnell JS, Szczepanski S, et al. Reactive neutrophil responses dependent on the receptor tyrosine kinase c-MET limit cancer immunotherapy. Immunity. 2017;47:789–802 e9.

  137. 137.

    Sukumaran S, Watanabe N, Bajgain P, Raja K, Mohammed S, Fisher WE. et al. Enhancing the potency and specificity of engineered T cells for cancer treatment. Cancer Discov. 2018;8:972–987.

  138. 138.

    Rosenberg SA. Progress in human tumour immunology and immunotherapy. Nature. 2001;411:380–4.

  139. 139.

    Gross G, Waks T, Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci USA. 1989;86:10024–8.

  140. 140.

    June CH, O’Connor RS, Kawalekar OU, Ghassemi S, Milone MC. CAR T cell immunotherapy for human cancer. Science. 2018;359:1361–5.

  141. 141.

    Bearoff F, Del Rio R, Case LK, Dragon JA, Nguyen-Vu T, Lin CY, et al. Natural genetic variation profoundly regulates gene expression in immune cells and dictates susceptibility to CNS autoimmunity. Genes Immun. 2016;17:386–95.

  142. 142.

    Furukawa H, Oka S, Tsuchiya N, Shimada K, Hashimoto A, Tohma S, et al. The role of common protective alleles HLA-DRB1*13 among systemic autoimmune diseases. Genes Immun. 2017;18:1–7.

  143. 143.

    Maldini CR, Ellis GI, Riley JL, CAR T. cells for infection, autoimmunity and allotransplantation. Nat Rev Immunol . 2018;18:605–616.

  144. 144.

    Kawalekar OU, O’Connor RS, Fraietta JA, Guo L, McGettigan SE, Posey AD Jr., et al. Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells. Immunity. 2016;44:380–90.

  145. 145.

    Horton B, Spranger S. A Tumor Cell-Intrinsic Yin-Yang Determining Immune Evasion. Immunity. 2018;49:11–13.

  146. 146.

    Anovazzi G, Medeiros MC, Pigossi SC, Finoti LS, Souza Moreira TM, Mayer MP, et al. Functionality and opposite roles of two interleukin 4 haplotypes in immune cells. Genes Immun. 2017;18:33–41.

  147. 147.

    Fielding CA, Jones GW, McLoughlin RM, McLeod L, Hammond VJ, Uceda J, et al. Interleukin-6 signaling drives fibrosis in unresolved inflammation. Immunity. 2014;40:40–50.

  148. 148.

    Marwaha AK, Panagiotopoulos C, Biggs CM, Staiger S, Del Bel KL, Hirschfeld AF, et al. Pre-diagnostic genotyping identifies T1D subjects with impaired Treg IL-2 signaling and an elevated proportion of FOXP3(+)IL-17(+) cells. Genes Immun. 2017;18:15–21.

  149. 149.

    Lovat PE, Ranalli M, Annichiarrico-Petruzzelli M, Bernassola F, Piacentini M, Malcolm AJ, et al. Effector mechanisms of fenretinide-induced apoptosis in neuroblastoma. Exp Cell Res. 2000;260:50–60.

  150. 150.

    Hu J, Sun C, Bernatchez C, Xia X, Hwu P, Dotti G, et al. T-cell homing therapy for reducing regulatory T Cells and preserving effector T-cell function in large solid tumors. Clin Cancer Res. 2018;24:2920–34.

  151. 151.

    Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M, et al. CD19 CAR-T cells of defined CD4+:CD8+composition in adult B cell ALL patients. J Clin Invest. 2016;126:2123–38.

Download references


This work has been supported by the Medical Research Council, UK; grants from Associazione Italiana per la Ricerca contro il Cancro (AIRC): AIRC 2017 IG20473 (to G.M.) and Fondazione Roma malattie Non trasmissibili Cronico-Degenerative (NCD) Grant (to G.M.).

Author information


  1. ENEA Research Center Casaccia, Laboratory of Biosafety and Risk Assessment, Via Anguillarese, 301, 00123, Rome, Italy

    • Giuseppe Raschellà
  2. Department of Experimental Medicine TOR, University of Rome “Tor Vergata”, Via Montpellier 1, 00133, Rome, Italy

    • Gerry Melino
    •  & Alessandra Gambacurta
  3. Medical Research Council, Toxicology Unit, Hodgkin Building, University of Cambridge, Leicester, LE1 9HN, UK

    • Gerry Melino


  1. Search for Giuseppe Raschellà in:

  2. Search for Gerry Melino in:

  3. Search for Alessandra Gambacurta in:

Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Giuseppe Raschellà.

About this article

Publication history