Skip to main content

Advertisement

SpringerLink
Log in

An essential role for the immune system in the mechanism of tumor regression following targeted oncogene inactivation

  • IMMUNOLOGY AT STANFORD UNIVERSITY
  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

Tumors are genetically complex and can have a multitude of mutations. Consequently, it is surprising that the suppression of a single oncogene can result in rapid and sustained tumor regression, illustrating the concept that cancers are often “oncogene addicted.” The mechanism of oncogene addiction has been presumed to be largely cell autonomous as a consequence of the restoration of normal physiological programs that induce proliferative arrest, apoptosis, differentiation, and/or cellular senescence. Interestingly, it has recently become apparent that upon oncogene inactivation, the immune response is critical in mediating the phenotypic consequences of oncogene addiction. In particular, CD4+ T cells have been suggested to be essential to the remodeling of the tumor microenvironment, including the shutdown of host angiogenesis and the induction of cellular senescence in the tumor. However, adaptive and innate immune cells are likely involved. Thus, the effectors of the immune system are involved not only in tumor initiation, tumor progression, and immunosurveillance, but also in the mechanism of tumor regression upon targeted oncogene inactivation. Hence, oncogene inactivation may be an effective therapeutic approach because it both reverses the neoplastic state within a cancer cell and reactivates the host immune response that remodels the tumor microenvironment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Jain M, Arvanitis C, Chu K, Dewey W, Leonhardt E, Trinh M, Sundberg CD, Bishop JM, Felsher DW. Sustained loss of a neoplastic phenotype by brief inactivation of MYC. Science. 2002;297:102–4.

    Article  CAS  PubMed  Google Scholar 

  2. Shachaf CM, Kopelman AM, Arvanitis C, Karlsson A, Beer S, Mandl S, Bachmann MH, Borowsky AD, Ruebner B, Cardiff RD, et al. MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. Nature. 2004;431:1112–7.

    Article  CAS  PubMed  Google Scholar 

  3. Hennighausen L, Wall RJ, Tillmann U, Li M, Furth PA. Conditional gene expression in secretory tissues and skin of transgenic mice using the MMTV-LTR and the tetracycline responsive system. J Cell Biochem. 1995;59:463–72.

    Article  CAS  PubMed  Google Scholar 

  4. Felsher DW, Bishop JM. Reversible tumorigenesis by MYC in hematopoietic lineages. Mol Cell. 1999;4:199–207.

    Article  CAS  PubMed  Google Scholar 

  5. Chin L, Tam A, Pomerantz J, Wong M, Holash J, Bardeesy N, Shen Q, O’Hagan R, Pantginis J, Zhou H, et al. Essential role for oncogenic Ras in tumour maintenance. Nature. 1999;400:468–72.

    Article  CAS  PubMed  Google Scholar 

  6. D’Cruz CM, Gunther EJ, Boxer RB, Hartman JL, Sintasath L, Moody SE, Cox JD, Ha SI, Belka GK, Golant A, et al. c-MYC induces mammary tumorigenesis by means of a preferred pathway involving spontaneous Kras2 mutations. Nat Med. 2001;7:235–9.

    Article  PubMed  Google Scholar 

  7. Fisher GH, Wellen SL, Klimstra D, Lenczowski JM, Tichelaar JW, Lizak MJ, Whitsett JA, Koretsky A, Varmus HE. Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes. Genes Dev. 2001;15:3249–62.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Huettner CS, Zhang P, Van Etten RA, Tenen DG. Reversibility of acute B-cell leukaemia induced by BCR-ABL1. Nat Genet. 2000;24:57–60.

    Article  CAS  PubMed  Google Scholar 

  9. Marinkovic D, Marinkovic T, Mahr B, Hess J, Wirth T. Reversible lymphomagenesis in conditionally c-MYC expressing mice. Int J Cancer. 2004;110:336–42.

    Article  CAS  PubMed  Google Scholar 

  10. Karlsson A, Giuriato S, Tang F, Fung-Weier J, Levan G, Felsher DW. Genomically complex lymphomas undergo sustained tumor regression upon MYC inactivation unless they acquire novel chromosomal translocations. Blood. 2003;101:2797–803.

    Article  CAS  PubMed  Google Scholar 

  11. Felsher DW. Cancer revoked: oncogenes as therapeutic targets. Nat Rev Cancer. 2003;3:375–80.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  13. Weinstein IB. Cancer. Addiction to oncogenes–the Achilles heal of cancer. Science. 2002;297:63–4.

    Article  CAS  PubMed  Google Scholar 

  14. Felsher DW: Oncogene addiction versus oncogene amnesia: perhaps more than just a bad habit? Cancer Res 2008, 68:3081–3086; discussion 3086.

  15. Kaelin WG Jr. The concept of synthetic lethality in the context of anticancer therapy. Nat Rev Cancer. 2005;5:689–98.

    Article  CAS  PubMed  Google Scholar 

  16. Sharma SV, Settleman J. Oncogene addiction: setting the stage for molecularly targeted cancer therapy. Genes Dev. 2007;21:3214–31.

    Article  CAS  PubMed  Google Scholar 

  17. Bozic I, Antal T, Ohtsuki H, Carter H, Kim D, Chen S, Karchin R, Kinzler KW, Vogelstein B, Nowak MA. Accumulation of driver and passenger mutations during tumor progression. Proc Natl Acad Sci USA. 2010;107:18545–50.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ, Shen D, Boca SM, Barber T, Ptak J, et al. The genomic landscapes of human breast and colorectal cancers. Science. 2007;318:1108–13.

    Article  CAS  PubMed  Google Scholar 

  19. Restifo NP. Can antitumor immunity help to explain “oncogene addiction”? Cancer Cell. 2010;18:403–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Furth PA. Cancer prevention as biomodulation: targeting the initiating stimulus and secondary adaptations. Ann N Y Acad Sci. 2012;1271:1–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Ding ZC, Huang L, Blazar BR, Yagita H, Mellor AL, Munn DH, Zhou G. Polyfunctional CD4(+) T cells are essential for eradicating advanced B-cell lymphoma after chemotherapy. Blood. 2012;120:2229–39.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Ding ZC, Zhou G. Cytotoxic chemotherapy and CD4+ effector T cells: an emerging alliance for durable antitumor effects. Clin Dev Immunol. 2012;2012:890178.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  23. Anders K, Buschow C, Herrmann A, Milojkovic A, Loddenkemper C, Kammertoens T, Daniel P, Yu H, Charo J, Blankenstein T. Oncogene-targeting T cells reject large tumors while oncogene inactivation selects escape variants in mouse models of cancer. Cancer Cell. 2011;20:755–67.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Zitvogel L, Kepp O, Kroemer G. Immune parameters affecting the efficacy of chemotherapeutic regimens. Nat Rev Clin Oncol. 2011;8:151–60.

    Article  CAS  PubMed  Google Scholar 

  25. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313:1960–4.

    Article  CAS  PubMed  Google Scholar 

  26. Dave SS, Wright G, Tan B, Rosenwald A, Gascoyne RD, Chan WC, Fisher RI, Braziel RM, Rimsza LM, Grogan TM, et al. Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med. 2004;351:2159–69.

    Article  CAS  PubMed  Google Scholar 

  27. Shortt J, Johnstone RW: Oncogenes in cell survival and cell death. Cold Spring Harb Perspect Biol. 2012;4(12).

  28. Baker SJ, Reddy EP. Targeted inhibition of kinases in cancer therapy. Mt Sinai J Med. 2010;77:573–86.

    Article  PubMed Central  PubMed  Google Scholar 

  29. Houshmand P, Zlotnik A. Targeting tumor cells. Curr Opin Cell Biol. 2003;15:640–4.

    Article  CAS  PubMed  Google Scholar 

  30. Blay JY, Le Cesne A, Alberti L, Ray-Coquart I. Targeted cancer therapies. Bull Cancer. 2005;92:E13–8.

    PubMed  Google Scholar 

  31. Soria JC, Blay JY, Spano JP, Pivot X, Coscas Y, Khayat D. Added value of molecular targeted agents in oncology. Ann Oncol. 2011;22:1703–16.

    Article  CAS  PubMed  Google Scholar 

  32. Nagai S, Takahashi T, Kurokawa M. The impact of molecularly targeted therapies upon the understanding of leukemogenesis and the role of hematopoietic stem cell transplantation in acute promyelocytic leukemia. Curr Stem Cell Res Ther. 2010;5:372–8.

    Article  CAS  PubMed  Google Scholar 

  33. Bollag G, Tsai J, Zhang J, Zhang C, Ibrahim P, Nolop K, Hirth P. Vemurafenib: the first drug approved for BRAF-mutant cancer. Nat Rev Drug Discov. 2012;11:873–86.

    Article  CAS  PubMed  Google Scholar 

  34. Casey SC, Bellovin DI, Felsher DW. Noncanonical roles of the immune system in eliciting oncogene addiction. Curr Opin Immunol. 2013;25:246–58.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Lindeman NI, Cagle PT, Beasley MB, Chitale DA, Dacic S, Giaccone G, Jenkins RB, Kwiatkowski DJ, Saldivar JS, Squire J, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the college of American pathologists, international association for the study of lung cancer, and association for molecular pathology. Arch Pathol Lab Med. 2013;137:828–60.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. O’Bryant CL, Wenger SD, Kim M, Thompson LA. Crizotinib: a new treatment option for ALK-positive non-small cell lung cancer. Ann Pharmacother. 2013;47:189–97.

    Article  PubMed  CAS  Google Scholar 

  37. Casaluce F, Sgambato A, Maione P, Rossi A, Ferrara C, Napolitano A, Palazzolo G, Ciardiello F, Gridelli C. ALK inhibitors: a new targeted therapy in the treatment of advanced NSCLC. Target Oncol. 2013;8:55–67.

    Article  PubMed  Google Scholar 

  38. Younes A, Romaguera J, Fanale M, McLaughlin P, Hagemeister F, Copeland A, Neelapu S, Kwak L, Shah J, De Castro Faria S, et al. Phase I study of a novel oral Janus kinase 2 inhibitor, SB1518, in patients with relapsed lymphoma: evidence of clinical and biologic activity in multiple lymphoma subtypes. J Clin Oncol. 2012;30:4161–7.

    Article  CAS  PubMed  Google Scholar 

  39. Cheok CF, Verma CS, Baselga J, Lane DP. Translating p53 into the clinic. Nat Rev Clin Oncol. 2011;8:25–37.

    Article  CAS  PubMed  Google Scholar 

  40. Essmann F, Schulze-Osthoff K. Translational approaches targeting the p53 pathway for anti-cancer therapy. Br J Pharmacol. 2012;165:328–44.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Fruman DA, Rommel C. PI3 Kdelta inhibitors in cancer: rationale and serendipity merge in the clinic. Cancer Discov. 2011;1:562–72.

    Article  CAS  PubMed  Google Scholar 

  42. Roschewski M, Farooqui M, Aue G, Wilhelm F, Wiestner A. Phase I study of ON 01910.Na (Rigosertib), a multikinase PI3K inhibitor in relapsed/refractory B-cell malignancies. Leukemia. 2013;27:1920–3.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Hong DS, Bowles DW, Falchook GS, Messersmith WA, George GC, O’Bryant CL, Vo AC, Klucher K, Herbst RS, Eckhardt SG, et al. A multicenter phase I trial of PX-866, an oral irreversible phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors. Clin Cancer Res. 2012;18:4173–82.

    Article  CAS  PubMed  Google Scholar 

  44. Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013;503:548–51.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Ott CJ, Kopp N, Bird L, Paranal RM, Qi J, Bowman T, Rodig SJ, Kung AL, Bradner JE, Weinstock DM. BET bromodomain inhibition targets both c-Myc and IL7R in high-risk acute lymphoblastic leukemia. Blood. 2012;120:2843–52.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, Kastritis E, Gilpatrick T, Paranal RM, Qi J, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146:904–17.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Hoeflich KP, Gray DC, Eby MT, Tien JY, Wong L, Bower J, Gogineni A, Zha J, Cole MJ, Stern HM, et al. Oncogenic BRAF is required for tumor growth and maintenance in melanoma models. Cancer Res. 2006;66:999–1006.

    Article  CAS  PubMed  Google Scholar 

  48. Boxer RB, Jang JW, Sintasath L, Chodosh LA. Lack of sustained regression of c-MYC-induced mammary adenocarcinomas following brief or prolonged MYC inactivation. Cancer Cell. 2004;6:577–86.

    Article  CAS  PubMed  Google Scholar 

  49. Giuriato S, Rabin K, Fan AC, Shachaf CM, Felsher DW. Conditional animal models: a strategy to define when oncogenes will be effective targets to treat cancer. Semin Cancer Biol. 2004;14:3–11.

    Article  CAS  PubMed  Google Scholar 

  50. Felsher DW. Reversing cancer from inside and out: oncogene addiction, cellular senescence, and the angiogenic switch. Lymphat Res Biol. 2008;6:149–54.

    Article  PubMed  Google Scholar 

  51. Shachaf CM, Felsher DW. Rehabilitation of cancer through oncogene inactivation. Trends Mol Med. 2005;11:316–21.

    Article  CAS  PubMed  Google Scholar 

  52. Shachaf CM, Felsher DW. Tumor dormancy and MYC inactivation: pushing cancer to the brink of normalcy. Cancer Res. 2005;65:4471–4.

    Article  CAS  PubMed  Google Scholar 

  53. Bellovin DI, Das B, Felsher DW. Tumor dormancy, oncogene addiction, cellular senescence, and self-renewal programs. Adv Exp Med Biol. 2013;734:91–107.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Giuriato S, Ryeom S, Fan AC, Bachireddy P, Lynch RC, Rioth MJ, van Riggelen J, Kopelman AM, Passegue E, Tang F, et al. Sustained regression of tumors upon MYC inactivation requires p53 or thrombospondin-1 to reverse the angiogenic switch. Proc Natl Acad Sci U S A. 2006;103:16266–71.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Baudino TA, McKay C, Pendeville-Samain H, Nilsson JA, Maclean KH, White EL, Davis AC, Ihle JN, Cleveland JL. c-Myc is essential for vasculogenesis and angiogenesis during development and tumor progression. Genes Dev. 2002;16:2530–43.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Brandvold KA, Neiman P, Ruddell A. Angiogenesis is an early event in the generation of myc-induced lymphomas. Oncogene. 2000;19:2780–5.

    Article  CAS  PubMed  Google Scholar 

  57. Janz A, Sevignani C, Kenyon K, Ngo CV, Thomas-Tikhonenko A. Activation of the myc oncoprotein leads to increased turnover of thrombospondin-1 mRNA. Nucleic Acids Res. 2000;28:2268–75.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Rakhra K, Bachireddy P, Zabuawala T, Zeiser R, Xu L, Kopelman A, Fan AC, Yang Q, Braunstein L, Crosby E, et al. CD4(+) T cells contribute to the remodeling of the microenvironment required for sustained tumor regression upon oncogene inactivation. Cancer Cell. 2010;18:485–98.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Albini A, Sporn MB. The tumour microenvironment as a target for chemoprevention. Nat Rev Cancer. 2007;7:139–47.

    Article  CAS  PubMed  Google Scholar 

  60. Coussens LM, Tinkle CL, Hanahan D, Werb Z. MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell. 2000;103:481–90.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  61. Bissell MJ, Radisky D. Putting tumours in context. Nat Rev Cancer. 2001;1:46–54.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, Schreiber RD. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature. 2001;410:1107–11.

    Article  CAS  PubMed  Google Scholar 

  63. de Visser KE, Korets LV, Coussens LM. De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell. 2005;7:411–23.

    Article  PubMed  CAS  Google Scholar 

  64. Dougan M, Li D, Neuberg D, Mihm M, Googe P, Wong KK, Dranoff G. A dual role for the immune response in a mouse model of inflammation-associated lung cancer. J Clin Invest. 2011;121:2436–46.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Ruffell B, DeNardo DG, Affara NI, Coussens LM. Lymphocytes in cancer development: polarization towards pro-tumor immunity. Cytokine Growth Factor Rev. 2010;21:3–10.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Gross E, Sunwoo JB, Bui JD. Cancer immunosurveillance and immunoediting by natural killer cells. Cancer J. 2013;19:483–9.

    Article  CAS  PubMed  Google Scholar 

  67. Torroella-Kouri M, Rodriguez D, Caso R. Alterations in macrophages and monocytes from tumor-bearing mice: evidence of local and systemic immune impairment. Immunol Res. 2013;57:86–98.

    Article  CAS  PubMed  Google Scholar 

  68. Iannello A, Raulet DH: Immune surveillance of unhealthy cells by natural killer cells. Cold Spring Harb Symp Quant Biol. 2013. doi:10.1101/sqb.2013.78.020255.

  69. Raj N, Attardi LD. Tumor suppression: p53 alters immune surveillance to restrain liver cancer. Curr Biol. 2013;23:R527–30.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  70. Gasser S, Raulet D. The DNA damage response, immunity and cancer. Semin Cancer Biol. 2006;16:344–7.

    Article  CAS  PubMed  Google Scholar 

  71. Chaturvedi AK, Pfeiffer RM, Chang L, Goedert JJ, Biggar RJ, Engels EA. Elevated risk of lung cancer among people with AIDS. AIDS. 2007;21:207–13.

    Article  PubMed  Google Scholar 

  72. Mbulaiteye SM, Biggar RJ, Goedert JJ, Engels EA. Immune deficiency and risk for malignancy among persons with AIDS. J Acquir Immune Defic Syndr. 2003;32:527–33.

    Article  PubMed  Google Scholar 

  73. Dugue PA, Rebolj M, Garred P, Lynge E. Immunosuppression and risk of cervical cancer. Expert Rev Anticancer Ther. 2013;13:29–42.

    Article  CAS  PubMed  Google Scholar 

  74. Kubica AW, Brewer JD. Melanoma in immunosuppressed patients. Mayo Clin Proc. 2012;87:991–1003.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  75. Hoover RN. Lymphoma risks in populations with altered immunity–a search for mechanism. Cancer Res. 1992;52:5477s–8s.

    CAS  PubMed  Google Scholar 

  76. Boshoff C, Weiss R. AIDS-related malignancies. Nat Rev Cancer. 2002;2:373–82.

    Article  CAS  PubMed  Google Scholar 

  77. Ray-Coquard I, Cropet C, Van Glabbeke M, Sebban C, Le Cesne A, Judson I, Tredan O, Verweij J, Biron P, Labidi I, et al. Lymphopenia as a prognostic factor for overall survival in advanced carcinomas, sarcomas, and lymphomas. Cancer Res. 2009;69:5383–91.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  78. Al-Tameemi M, Chaplain M, d’Onofrio A. Evasion of tumours from the control of the immune system: consequences of brief encounters. Biol Direct. 2012;7:31.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  79. Ribas A. Immunoediting the cancer genome–a new approach for personalized cancer therapy? Pigment Cell Melanoma Res. 2012;25:297–8.

    Article  PubMed  Google Scholar 

  80. Peggs KS, Quezada SA, Allison JP. Cell intrinsic mechanisms of T-cell inhibition and application to cancer therapy. Immunol Rev. 2008;224:141–65.

    Article  CAS  PubMed  Google Scholar 

  81. Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat Rev Immunol. 2006;6:715–27.

    Article  CAS  PubMed  Google Scholar 

  82. Martins I, Wang Y, Michaud M, Ma Y, Sukkurwala AQ, Shen S, Kepp O, Metivier D, Galluzzi L, Perfettini JL, et al. Molecular mechanisms of ATP secretion during immunogenic cell death. Cell Death Differ. 2014;21:79–91.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  83. Vacchelli E, Senovilla L, Eggermont A, Fridman WH, Galon J, Zitvogel L, Kroemer G, Galluzzi L. Trial watch: chemotherapy with immunogenic cell death inducers. Oncoimmunology. 2013;2:e23510.

    Article  PubMed Central  PubMed  Google Scholar 

  84. Maloney DG, Grillo-Lopez AJ, White CA, Bodkin D, Schilder RJ, Neidhart JA, Janakiraman N, Foon KA, Liles TM, Dallaire BK, et al. IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma. Blood. 1997;90:2188–95.

    CAS  PubMed  Google Scholar 

  85. Pegram MD, Konecny G, Slamon DJ. The molecular and cellular biology of HER2/neu gene amplification/overexpression and the clinical development of herceptin (trastuzumab) therapy for breast cancer. Cancer Treat Res. 2000;103:57–75.

    Article  CAS  PubMed  Google Scholar 

  86. Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L, Perfettini JL, Castedo M, Mignot G, Panaretakis T, Casares N, et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med. 2007;13:54–61.

    Article  CAS  PubMed  Google Scholar 

  87. Shiao SL, Coussens LM. The tumor-immune microenvironment and response to radiation therapy. J Mammary Gland Biol Neoplasia. 2010;15:411–21.

    Article  PubMed Central  PubMed  Google Scholar 

  88. Pardoll DM. Immunology beats cancer: a blueprint for successful translation. Nat Immunol. 2012;13:1129–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Acharya UH, Jeter JM. Use of ipilimumab in the treatment of melanoma. Clin Pharmacol. 2013;5:21–7.

    PubMed Central  PubMed  Google Scholar 

  90. Devaud C, John LB, Westwood JA, Darcy PK, Kershaw MH. Immune modulation of the tumor microenvironment for enhancing cancer immunotherapy. Oncoimmunology. 2013;2:e25961.

    Article  PubMed Central  PubMed  Google Scholar 

  91. Chao MP, Weissman IL, Majeti R. The CD47-SIRPalpha pathway in cancer immune evasion and potential therapeutic implications. Curr Opin Immunol. 2012;24:225–32.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  92. Parsa AT, Waldron JS, Panner A, Crane CA, Parney IF, Barry JJ, Cachola KE, Murray JC, Tihan T, Jensen MC, et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med. 2007;13:84–8.

    Article  CAS  PubMed  Google Scholar 

  93. Mattarollo SR, West AC, Steegh K, Duret H, Paget C, Martin B, Matthews GM, Shortt J, Chesi M, Bergsagel PL, et al. NKT cell adjuvant-based tumor vaccine for treatment of myc oncogene-driven mouse B-cell lymphoma. Blood. 2012;120:3019–29.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  94. Kawakami Y, Yaguchi T, Sumimoto H, Kudo-Saito C, Tsukamoto N, Iwata-Kajihara T, Nakamura S, Nishio H, Satomi R, Kobayashi A, et al. Cancer-induced immunosuppressive cascades and their reversal by molecular-targeted therapy. Ann N Y Acad Sci. 2013;1284:80–6.

    Article  CAS  PubMed  Google Scholar 

  95. Gossen M, Bujard H. Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc Natl Acad Sci U S A. 1992;89:5547–51.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  96. Lawler PR, Lawler J. Molecular basis for the regulation of angiogenesis by thrombospondin-1 and -2. Cold Spring Harb Perspect Med. 2012;2:a006627.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  97. Li SS, Liu Z, Uzunel M, Sundqvist KG. Endogenous thrombospondin-1 is a cell-surface ligand for regulation of integrin-dependent T-lymphocyte adhesion. Blood. 2006;108:3112–20.

    Article  CAS  PubMed  Google Scholar 

  98. Baek KH, Bhang D, Zaslavsky A, Wang LC, Vachani A, Kim CF, Albelda SM, Evan GI, Ryeom S. Thrombospondin-1 mediates oncogenic Ras-induced senescence in premalignant lung tumors. J Clin Invest. 2013;123:4375–89.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  99. Sosale N, Discher DE. Marker-of-self becomes marker-of-senescence. Blood. 2012;119:5343–4.

    Article  CAS  PubMed  Google Scholar 

  100. Acosta JC, O’Loghlen A, Banito A, Guijarro MV, Augert A, Raguz S, Fumagalli M, Da Costa M, Brown C, Popov N, et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell. 2008;133:1006–18.

    Article  CAS  PubMed  Google Scholar 

  101. Beatty G, Paterson Y. IFN-gamma-dependent inhibition of tumor angiogenesis by tumor-infiltrating CD4 + T cells requires tumor responsiveness to IFN-gamma. J Immunol. 2001;166:2276–82.

    Article  CAS  PubMed  Google Scholar 

  102. Kuilman T, Michaloglou C, Vredeveld LC, Douma S, van Doorn R, Desmet CJ, Aarden LA, Mooi WJ, Peeper DS. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell. 2008;133:1019–31.

    Article  CAS  PubMed  Google Scholar 

  103. Muller-Hermelink N, Braumuller H, Pichler B, Wieder T, Mailhammer R, Schaak K, Ghoreschi K, Yazdi A, Haubner R, Sander CA, et al. TNFR1 signaling and IFN-gamma signaling determine whether T cells induce tumor dormancy or promote multistage carcinogenesis. Cancer Cell. 2008;13:507–18.

    Article  PubMed  CAS  Google Scholar 

  104. Whitfield JR, Soucek L. Tumor microenvironment: becoming sick of Myc. Cell Mol Life Sci. 2012;69:931–4.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  105. Galluzzi L, Vitale I, Kroemer G. Past, present, and future of molecular and cellular oncology. Front Oncol. 2011;1:1.

    PubMed Central  PubMed  Google Scholar 

  106. Somasundaram R, Villanueva J, Herlyn M. Intratumoral heterogeneity as a therapy resistance mechanism: role of melanoma subpopulations. Adv Pharmacol. 2012;65:335–59.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  107. Al-Ejeh F, Smart CE, Morrison BJ, Chenevix-Trench G, Lopez JA, Lakhani SR, Brown MP, Khanna KK. Breast cancer stem cells: treatment resistance and therapeutic opportunities. Carcinogenesis. 2011;32:650–8.

    Article  CAS  PubMed  Google Scholar 

  108. Soucek L, Lawlor ER, Soto D, Shchors K, Swigart LB, Evan GI. Mast cells are required for angiogenesis and macroscopic expansion of Myc-induced pancreatic islet tumors. Nat Med. 2007;13:1211–8.

    Article  CAS  PubMed  Google Scholar 

  109. Reimann M, Lee S, Loddenkemper C, Dorr JR, Tabor V, Aichele P, Stein H, Dorken B, Jenuweins T, Schmitt CA. Tumor stroma-derived TGF-beta limits myc-driven lymphomagenesis via Suv39h1-dependent senescence. Cancer Cell. 2010;17:262–72.

    Article  CAS  PubMed  Google Scholar 

  110. Kerkar SP, Muranski P, Kaiser A, Boni A, Sanchez-Perez L, Yu Z, Palmer DC, Reger RN, Borman ZA, Zhang L, et al. Tumor-specific CD8 + T cells expressing interleukin-12 eradicate established cancers in lymphodepleted hosts. Cancer Res. 2010;70:6725–34.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  111. Zhang L, Yu Z, Muranski P, Palmer DC, Restifo NP, Rosenberg SA, Morgan RA: Inhibition of TGF-beta signaling in genetically engineered tumor antigen-reactive T cells significantly enhances tumor treatment efficacy. Gene Ther. 2013;20(5):575–80.

  112. Gattinoni L, Klebanoff CA, Restifo NP. Paths to stemness: building the ultimate antitumour T cell. Nat Rev Cancer. 2012;12:671–84.

    Article  CAS  PubMed  Google Scholar 

  113. Klebanoff CA, Gattinoni L, Restifo NP. Sorting through subsets: which T-cell populations mediate highly effective adoptive immunotherapy? J Immunother. 2012;35:651–60.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  114. Mlecnik B, Tosolini M, Kirilovsky A, Berger A, Bindea G, Meatchi T, Bruneval P, Trajanoski Z, Fridman WH, Pages F, et al. Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. J Clin Oncol. 2011;29:610–8.

    Article  PubMed  Google Scholar 

  115. Prestwich RJ, Errington F, Hatfield P, Merrick AE, Ilett EJ, Selby PJ, Melcher AA. The immune system–is it relevant to cancer development, progression and treatment? Clin Oncol (R Coll Radiol). 2008;20:101–12.

    Article  CAS  Google Scholar 

  116. Hannani D, Sistigu A, Kepp O, Galluzzi L, Kroemer G, Zitvogel L. Prerequisites for the antitumor vaccine-like effect of chemotherapy and radiotherapy. Cancer J. 2011;17:351–8.

    Article  CAS  PubMed  Google Scholar 

  117. Ma Y, Kepp O, Ghiringhelli F, Apetoh L, Aymeric L, Locher C, Tesniere A, Martins I, Ly A, Haynes NM, et al. Chemotherapy and radiotherapy: cryptic anticancer vaccines. Semin Immunol. 2010;22:113–24.

    Article  PubMed  CAS  Google Scholar 

  118. Dougan M, Dranoff G. Immune therapy for cancer. Annu Rev Immunol. 2009;27:83–117.

    Article  CAS  PubMed  Google Scholar 

  119. Menard C, Blay JY, Borg C, Michiels S, Ghiringhelli F, Robert C, Nonn C, Chaput N, Taieb J, Delahaye NF, et al. Natural killer cell IFN-gamma levels predict long-term survival with imatinib mesylate therapy in gastrointestinal stromal tumor-bearing patients. Cancer Res. 2009;69:3563–9.

    Article  CAS  PubMed  Google Scholar 

  120. Wilmott JS, Long GV, Howle JR, Haydu LE, Sharma RN, Thompson JF, Kefford RF, Hersey P, Scolyer RA. Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma. Clin Cancer Res. 2012;18:1386–94.

    Article  CAS  PubMed  Google Scholar 

  121. Wilmott JS, Scolyer RA, Long GV, Hersey P. Combined targeted therapy and immunotherapy in the treatment of advanced melanoma. Oncoimmunology. 2012;1:997–9.

    Article  PubMed Central  PubMed  Google Scholar 

  122. Liu C, Peng W, Xu C, Lou Y, Zhang M, Wargo JA, Chen J, Li HS, Watowich S, Yang Y, et al.: BRAF inhibition increases tumor infiltration by T cells and enhances the anti-tumor activity of adoptive immunotherapy in mice. Clin Cancer Res. 2013;19(2):393–403.

  123. Sumimoto H, Imabayashi F, Iwata T, Kawakami Y. The BRAF-MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells. J Exp Med. 2006;203:1651–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  124. Bajor DL, Vonderheide RH. Rehabilitation for oncogene addiction: role of immunity in cellular sobriety. Clin Cancer Res. 2012;18:1192–4.

    Article  PubMed  Google Scholar 

  125. Knight DA, Ngiow SF, Li M, Parmenter T, Mok S, Cass A, Haynes NM, Kinross K, Yagita H, Koya RC, et al. Host immunity contributes to the anti-melanoma activity of BRAF inhibitors. J Clin Invest. 2013;123:1371–81.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  126. Bex A, Etto T, Vyth-Dreese F, Blank C, Griffioen AW. Immunological heterogeneity of the RCC microenvironment: do targeted therapies influence immune response? Curr Oncol Rep. 2012;14:230–9.

    Article  CAS  PubMed  Google Scholar 

  127. Finke JH, Rini B, Ireland J, Rayman P, Richmond A, Golshayan A, Wood L, Elson P, Garcia J, Dreicer R, et al. Sunitinib reverses type-1 immune suppression and decreases T-regulatory cells in renal cell carcinoma patients. Clin Cancer Res. 2008;14:6674–82.

    Article  CAS  PubMed  Google Scholar 

  128. Busse A, Asemissen AM, Nonnenmacher A, Braun F, Ochsenreither S, Stather D, Fusi A, Schmittel A, Miller K, Thiel E, et al. Immunomodulatory effects of sorafenib on peripheral immune effector cells in metastatic renal cell carcinoma. Eur J Cancer. 2011;47:690–6.

    Article  CAS  PubMed  Google Scholar 

  129. Zhang H, Melamed J, Wei P, Cox K, Frankel W, Bahnson RR, Robinson N, Pyka R, Liu Y, Zheng P. Concordant down-regulation of proto-oncogene PML and major histocompatibility antigen HLA class I expression in high-grade prostate cancer. Cancer Immun. 2003;3:2.

    PubMed  Google Scholar 

  130. Chang CL, Hsu YT, Wu CC, Yang YC, Wang C, Wu TC, Hung CF. Immune mechanism of the antitumor effects generated by bortezomib. J Immunol. 2012;189:3209–20.

    Article  CAS  PubMed  Google Scholar 

  131. Guttman-Yassky E, Mita A, De Jonge M, Matthews L, McCarthy S, Iwata KK, Verweij J, Rowinsky EK, Krueger JG. Characterisation of the cutaneous pathology in non-small cell lung cancer (NSCLC) patients treated with the EGFR tyrosine kinase inhibitor erlotinib. Eur J Cancer. 2010;46:2010–9.

    Article  CAS  PubMed  Google Scholar 

  132. Jaime-Ramirez AC, Mundy-Bosse BL, Kondadasula S, Jones NB, Roda JM, Mani A, Parihar R, Karpa V, Papenfuss TL, LaPerle KM, et al. IL-12 enhances the antitumor actions of trastuzumab via NK cell IFN-gamma production. J Immunol. 2011;186:3401–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  133. Kohrt HE, Houot R, Weiskopf K, Goldstein MJ, Scheeren F, Czerwinski D, Colevas AD, Weng WK, Clarke MF, Carlson RW, et al. Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer. J Clin Invest. 2012;122:1066–75.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  134. Boni A, Cogdill AP, Dang P, Udayakumar D, Njauw CN, Sloss CM, Ferrone CR, Flaherty KT, Lawrence DP, Fisher DE, et al. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res. 2010;70:5213–9.

    Article  CAS  PubMed  Google Scholar 

  135. Catellani S, Pierri I, Gobbi M, Poggi A, Zocchi MR. Imatinib treatment induces CD5 + B lymphocytes and IgM natural antibodies with anti-leukemic reactivity in patients with chronic myelogenous leukemia. PLoS ONE. 2011;6:e18925.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  136. Krusch M, Salih HR. Effects of BCR-ABL inhibitors on anti-tumor immunity. Curr Med Chem. 2011;18:5174–84.

    Article  CAS  PubMed  Google Scholar 

  137. Ohyashiki K, Katagiri S, Tauchi T, Ohyashiki JH, Maeda Y, Matsumura I, Kyo T. Increased natural killer cells and decreased CD3(+)CD8(+)CD62L(+) T cells in CML patients who sustained complete molecular remission after discontinuation of imatinib. Br J Haematol. 2012;157:254–6.

    Article  CAS  PubMed  Google Scholar 

  138. Kreutzman A, Juvonen V, Kairisto V, Ekblom M, Stenke L, Seggewiss R, Porkka K, Mustjoki S. Mono/oligoclonal T and NK cells are common in chronic myeloid leukemia patients at diagnosis and expand during dasatinib therapy. Blood. 2010;116:772–82.

    Article  CAS  PubMed  Google Scholar 

  139. Chen J, Schmitt A, Giannopoulos K, Chen B, Rojewski M, Dohner H, Bunjes D, Schmitt M. Imatinib impairs the proliferation and function of CD4 + CD25 + regulatory T cells in a dose-dependent manner. Int J Oncol. 2007;31:1133–9.

    CAS  PubMed  Google Scholar 

  140. Blank CU, Hooijkaas AI, Haanen JB, Schumacher TN. Combination of targeted therapy and immunotherapy in melanoma. Cancer Immunol Immunother. 2011;60:1359–71.

    Article  PubMed  Google Scholar 

  141. Wrzesinski C, Paulos CM, Kaiser A, Muranski P, Palmer DC, Gattinoni L, Yu Z, Rosenberg SA, Restifo NP. Increased intensity lymphodepletion enhances tumor treatment efficacy of adoptively transferred tumor-specific T cells. J Immunother. 2010;33:1–7.

    Article  PubMed Central  PubMed  Google Scholar 

  142. Humphrey RW, Brockway-Lunardi LM, Bonk DT, Dohoney KM, Doroshow JH, Meech SJ, Ratain MJ, Topalian SL, Pardoll DM. Opportunities and challenges in the development of experimental drug combinations for cancer. J Natl Cancer Inst. 2011;103:1222–6.

    Article  CAS  PubMed  Google Scholar 

  143. Vanneman M, Dranoff G. Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer. 2012;12:237–51.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  144. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480:480–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors acknowledge current and former members of the Felsher laboratory. Within the Felsher laboratory, research has been funded by the Burroughs Welcome Fund Career Award, the Damon Runyon Foundation Lilly Clinical Investigator Award, NIH RO1 Grant Number CA 089305, 105102, 170378 PQ22, U54CA149145, U54CA143907, National Cancer Institute’s In-vivo Cellular and Molecular Imaging Center Grant Number CA 114747, Integrative Cancer Biology Program Grant Number CA 112973, NIH/NCI PO1 Grant Number CA034233, and the Leukemia and Lymphoma Society Translational Research Grant Number R6223-07 (D.W.F.). S.C.C. was previously supported by the Stanford University Cellular and Molecular Immunobiology Training Grant (NIH, 5 T32 AI07290) and is currently supported by an NIH NRSA from the NCI (F32CA177139).

Conflict of interests

The authors declare no competing financial interests.

Author information

Authors and Affiliations

  1. Division of Oncology, Departments of Medicine and Pathology, Stanford University School of Medicine, 269 Campus Drive, CCSR 1105, Stanford, CA, 94305-5151, USA

    Stephanie C. Casey, Yulin Li & Dean W. Felsher

Authors
  1. Stephanie C. Casey
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yulin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dean W. Felsher
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dean W. Felsher.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Casey, S.C., Li, Y. & Felsher, D.W. An essential role for the immune system in the mechanism of tumor regression following targeted oncogene inactivation. Immunol Res 58, 282–291 (2014). https://doi.org/10.1007/s12026-014-8503-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-014-8503-6

Keywords

Search

Navigation